Wellcome to the PBPath Journal Watch!
This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, cytopathology, and molecular pathology among others. The articles in each category are in no particular order.
Previous months’ issues may be found in our archive.
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Morphology, Diagnostics, IHC
- Malformations, choristomas, and hamartomas of the gastrointestinal tract and pancreas
Seminars in diagnostic pathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30482417
Congenital and hamartomatous lesions of the gastrointestinal tract cause diagnostic challenges for surgical pathologists. Many of these are merely histologic curiosities, whereas others have substantial clinical implications because they herald cancer syndromes or associated anomalies. Although a comprehensive discussion of all developmental abnormalities that can occur in the gastrointestinal tract is beyond the scope of a single manuscript, some entities are more likely to be encountered by surgical pathologists, have important clinical consequences, or pose diagnostic difficulties. The purpose of this review is to discuss the more common malformations and choristomas, as well as hamartomatous lesions that may be clinically important due to their risk for cancer development, frequent associations with heritable cancer syndromes and other anomalies, or potential to simulate other entities.
- AQP1 and AQP3 Expression are Associated With Severe Symptoms and Poor-prognosis of the Pancreatic Ductal Adenocarcinoma
Applied immunohistochemistry & molecular morphology : AIMM 2019 Jan;27(1):40-47
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531392
BACKGROUND: Approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease with poor prognosis, but clinically available biomarkers for the diagnosis, prediction of prognosis, and target therapy have not yet been identified. OBJECTIVE: To investigate the expression of aquaporin-1 (AQP1) and AQP3 protein and their clinicopathological significances in PDACs. MATERIALS AND METHOD: AQP1 and AQP3 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues was measured by immunohistochemistry. RESULTS: Western blot showed that AQP1 and AQP3 protein expression was significantly higher in PDAC tissues than that in benign pancreatic tissues (P<0.01). Immunohistochemistry showed that the percentages of positive AQP1 and AQP3 expressions were significantly higher in PDAC tumors than that in peritumoral tissues, benign, and normal pancreatic tissues (P<0.01). Benign pancreatic lesions with positive AQP1 and AQP3 expression exhibited a dysplasia or intraepithelial neoplasia. The percentage of cases with positive AQP1 and AQP3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion, and having low Tumor, Node and Metastasis (TNM) stage disease than in patients with lymph node metastasis, invasion, and high TNM stage disease (P<0.05 or <0.01). Kaplan-Meier survival analysis showed that positive AQP1 and AQP3 expression were significantly associated with survival in PDAC patients (P<0.001). Cox multivariate analysis revealed that positive AQP1 and AQP3 expression was independent poor prognosis factors in PDAC patients. The area under the curve of receiver operating characteristic curve was 0.669 for AQP1 and 0.707 for AQP3, respectively. CONCLUSIONS: Positive AQP1 and AQP3 expressions are associated with the tumorigenesis and progression of PDAC. Both AQP1 and AQP3 are a diagnostic marker of PDAC and a predictive marker of poor prognosis in PDAC patients.
- Clinicopathologic and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma
Human pathology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30537492
Mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7) were shown to regulate biological behavior in many malignancies. In pancreatic ductal adenocarcinoma (PDAC), it remains controversial whether MKK4 and MKK7 have pro-oncogenic or tumor-suppressive activities. Furthermore, their clinicopathologic and prognostic implications are unknown. In the present study, we detected MKK4 and MKK7 expressions in the nucleus and cytoplasm of resected PDAC tissues from 321 patients by tissue microarray-based immunohistochemistry. Cytoplasmic MKK4 and MKK7 expressions were significantly down-regulated, while nuclear MKK4 expression was significantly up-regulated in tumor tissues compared with non-tumor tissues. Tumor cytoplasmic MKK4 and MKK7 expressions were significantly negatively associated with histological grade. Cytoplasmic MKK4 expression was also negatively correlated with CA19-9 level. By univariate analysis, high cytoplasmic MKK4 expression was significantly associated with longer cancer-specific survival (hazard ratio [HR]: 0.705; 95% confidence interval [95%CI]: 0.510-0.974), with a similar trend observed for MKK7 expression. High MKK4 and MKK7 mRNA expressions were significantly associated with longer overall survival in the TCGA database. Although MKK4 expression was not significant in a multivariate Cox regression analysis, combination of MKK4/MKK7 and pN stage was identified as an independent prognostic indicator and had the lowest HR (HR: 0.308; 95%CI: 0.126-0.752). Furthermore, combined analysis of MKK4 and MKK7 greatly increased the prognostic predictive power. In addition, down-regulation of MKK4 or MKK7 increased proliferation of pancreatic cancer cells in vitro. In conclusion, high MKK4 expression and its combination with high MKK7 expression both predicted favorable prognosis in resectable PDAC.
- PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 expression is limited to the squamous component
Pathology, research and practice 2018 Dec;214(12):2069-2074
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30477643
AIM: We examined the programmed death-ligand 1 (PD-L1) expression in surgically resected pancreatic adenosquamous carcinoma (PASC) samples. Furthermore, the detection rate was also assessed using biopsy cases obtained from endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). METHODS: Fifteen cases of PASC (six resected and nine EUS-FNA biopsied) from the Kurume University Hospital between 2009 and 2016 were used for the evaluation of PD-L1 expression. As a control group, 34 cases of pancreatic ductal adenocarcinomas (PDACs) were selected. To compare the positivity and intensity of PD-L1, two types of clones (SP263, E1L3N) were examined for immunostaining. Only the membrane expression of PD-L1 was regarded as positive. The PD-L1 expressions in the squamous cell carcinoma component (SCc), adenocarcinoma component (ACc), and immune cells were assessed separately. The ratio of PD-L1 expression was calculated by counting the positive tumor cells, and tumor proportion score (TPS) was applied (TPS; Null < 1%, low expression; 1 ≤ TPS ≤ 49% and high expression; ≥ 50%). RESULTS: PD-L1 expression was observed in five surgical PASC samples (83%). This shows that SCc presented a high expression in these cases. However, the overall TPS indicated a low expression. In contrast, only one case (3%) was positive for PD-L1 in PDACs, and the TPS indicated a low expression. No differences in PD-L1 expression were observed between the two clones, SP263 and E1L3N. High PD-L1 expression in the EUS-FNA sample was found in only one case (11%). DISCUSSION: Although assessment using the tumor cells of PASC samples obtained from EUS-FNA was difficult, this study suggests the selective expression of PD-L1 in the SCc of PASC. Furthermore, it was considered that immune checkpoint inhibitors could provide therapeutic effects selectively on the SCc for the entire range of TPSs, though the PD-L1 expression was low.
- Pancreatic Ductal Adenocarcinoma: Recent Updates
The American journal of pathology 2019 Jan;189(1):6-8
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558724
This Guest Editorial introduces this month’s special Pancreatic Cancer Theme Issue, a series of reviews intended to highlight the pathologic to molecular profiles and diagnoses of benign and neoplastic pancreatic lesions.
- Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions: Histopathology, Cytopathology, and Molecular Pathology
The American journal of pathology 2019 Jan;189(1):9-21
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558727
Pancreatic ductal adenocarcinoma is one of the most aggressive malignant neoplasms with poor outcomes. At the time of diagnosis, the disease is usually at an advanced stage and only a minority is eligible for surgical resection. To improve the prognosis, it is essential to diagnose and treat the disease in an early stage before its progression into an invasive disease. This article reviews clinical features, histopathology, cytopathology, and molecular alterations of pancreatic ductal adenocarcinoma and its precursors. Moreover, we review a recently updated two-tier classification system for precursor lesions, new findings in premalignant cystic neoplasms, and recently updated staging criteria for invasive carcinoma based on the Cancer Staging Manual, eighth edition, from the American Joint Committee on Cancer. Finally, we discuss the potential clinical applications of the rapidly growing molecular and genetic information of pancreatic cancer and its precursors.
- Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer
Annals of surgery 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30570546
OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.
- Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients
Medical molecular morphology 2018 Jun;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29926190
Pancreatic cancer has a poor prognosis; hence, novel prognostic markers and effective therapeutic targets should be identified. We aimed to evaluate folate receptor alpha (FR-α) expression in pancreatic cancer and examine its association with clinicopathological features. We utilized tissue samples from 100 primary pancreatic cancer patients who underwent surgery. FR-α was expressed in 37 of 100 cases (37%). The FR-α-positive group (median, 18.8 months) had a significantly poorer prognosis than the FR-α-negative group [median 21.3 months; HR 1.89 (1.12-3.12); P = 0.017]. These groups were not significantly different regarding progression-free survival (P = 0.196). Furthermore, other serum tumor markers including CA19-9 (mean, 186 vs. 822 U/ml; P = 0.001), Dupan-2 (286 vs. 1133 U/ml; P = 0.000), and Span-1 (69.7 vs. 171.9 U/ml; P = 0.006) were significantly downregulated in the FR-α-positive group. CA19-9 was another prognostic factor, in addition to FR-α, and patient prognosis showed clear stratification curves with the expression of these two molecules. Along with CA19-9, FR-α expression was an independent prognostic factor for the overall survival. FR-α and CA19-9 helped predict patient prognosis based on stratification curves.
Pancreas TNM staging, Margins, Survival
- Measured residual tumor cellularity correlates with survival in neoadjuvant treated pancreatic ductal adenocarcinomas
Annals of diagnostic pathology 2018 Nov;38():93-98
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30562721
- Application of the Eighth Edition of the American Joint Committee on Cancer Staging for Pancreatic Adenocarcinoma
Pancreas 2018 07;47(6):742-747
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29851752
OBJECTIVES: Notable modifications have been made in the American Joint Committee on Cancer (AJCC) Staging eighth edition staging for pancreatic cancer for the consideration of the irreproducible and inapplicable of the AJCC seventh edition staging. However, the new staging classification has not been systemically verified. METHODS: A comparison was performed to evaluate the application of the AJCC seventh and eighth staging classifications using the Surveillance, Epidemiology, and End Results registry (18,450 patients) and an institutional series (2040 patients). RESULTS: For the eighth staging classification, patients with tumor diameter of greater than 4 cm (T3N0M0, IIA) had similar prognosis to patients with 1 to 3 positive nodes (T1-3N1M0, IIB). For patients who underwent tumor resection and without lymph node involvement, survival curves of T1 (≤2 cm), T2 (2-4 cm), and T3 (>4 cm) were well separated. Statistical difference in survival analyses was demonstrated in N0 (0 positive node), N1 (1-3 positive nodes), and N2 (≥4 positive nodes) patients underwent tumor resection. The AJCC eighth edition had better stage distribution than the AJCC seventh edition for pancreatic cancer. CONCLUSIONS: The eighth edition of AJCC staging is more applicable and accurate than the seventh edition for pancreatic adenocarcinoma.
- Prognostic significance of the degree of lymphatic vessel invasion in locally advanced, surgically resectable pancreatic head cancer: A single center experience
Medicine 2018 Dec;97(49):e13466
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30544433
Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ≥5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ≥7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ≥9 and ≥10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30 mm, duodenal invasion, LN metastasis and an LVI-score ≥2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ≥9 and ≥10 were significantly associated with poor overall survival, and an LVI-score ≥10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.
- Multinational validation of the American Joint Committee on Cancer 8th edition pancreatic cancer staging system in a pancreas head cancer cohort
Journal of hepato-biliary-pancreatic sciences 2018 Sep;25(9):418-427
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30118171
BACKGROUND: The aim of the present study was to compare the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system for pancreas head cancer and to validate the 8th edition using three multinational tertiary center data. METHODS: Data of 2,864 patients with pancreas head cancer were collected from Korea (571), Japan (824), and the USA (1,469). Survival analysis was performed to compare the 7th and 8th editions. Validation was performed by log-rank tests and test for trend repeated 1,000 times with random sets. RESULTS: In the 7th edition, 4.1%, 3.1%, 18.6%, 67.5%, 3.6%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV. In the 8th edition, 8.8%, 13.9%, 3.1%, 38.2%, 32.9%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV, respectively. The change in T category downstaged 459 patients from IIA to the new IA and IB. The new N2 category upstaged 856 patients from the former IIB to III. The 7th edition reversely stratified IA and IB. The 8th edition corrected this mis-stratification of the 7th edition, but lacked discriminatory power between IB and IIA (P = 0.271). Validation using the log-rank showed that the 8th edition provided better discrimination in 6.387 test sets among 10 tests. The test for trend validated the 8th edition to stratify stages in correct order more often (7.815/10). CONCLUSION: The 8th edition provides more even distribution with more powerful discrimination compared to the 7th edition.
Preneoplastic and Preinvasive Lesions, PanIN, IPMN, MCN, ICPN
- New Model for Predicting Malignancy in Patients With Intraductal Papillary Mucinous Neoplasm
Annals of surgery 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499803
OBJECTIVE: To create a simple, objective model to predict the presence of malignancy in patients with intraductal papillary mucinous neoplasm (IPMN), which can be easily applied in daily practice and, importantly, adopted for any lesion types. BACKGROUND: No predictive model for malignant IPMN has been widely applied in clinical practice. METHODS: The clinical details of 466 patients with IPMN who underwent pancreatic resection at 3 hospitals were retrospectively analyzed for model development. Then, the model was validated in 664 surgically resected patients at 8 hospitals in Japan.In the preoperative examination, endoscopic ultrasonography (EUS) was considered to be essential to observe mural nodules in both the model development and external validation sets. Malignant IPMNs were defined as those with high-grade dysplasia and associated invasive carcinoma. RESULTS: Of the 466 patients, 258 (55%) had malignant IPMNs (158 high-grade dysplasia, 100 invasive carcinoma), and 208 (45%) had benign IPMNs. Logistic regression analysis resulted in 3 variables (mural nodule size, main pancreatic duct diameter, and cyst size) being selected to construct the model. The area under the receiver operating characteristic curve (AUC) for the model was 0.763. In external validation sets, the pathological diagnosis was malignant and benign IPMN in 351 (53%) and 313 (47%) cases, respectively. For the external validation, the malignancy prediction ability of the model corresponded to an AUC of 0.725. CONCLUSION: This predictive model provides important information for physicians and patients in assessing an individual’s risk for malignancy and may help to identify patients who need surgery.
- Subtyping of intraductal papillary mucinous neoplasms - pitfalls of MUC1 immunohistochemistry
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 2019 Jan;127(1):27-32
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30549137
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Current edition of WHO Classification of Tumors of the Digestive System recognizes four different subtypes (gastric, intestinal, pancreatobiliary, and oncocytic) and recommends analysis of mucin expression (MUC1, MUC2, MUC5AC, MUC6) as well as evaluation of architectural and cell differentiation patterns for correct classification. However, there is no consensus on MUC1 expression of IPMN-lesions in the literature. Current recommendations are based on studies where antibodies against the core MUC1 protein or sialylated MUC1 (tumor associated MUC1), not the fully glycosylated MUC1 were used. We have recently reported that MUC1 is strongly expressed in both gastric and intestinal types IPMN specimens from the cystic wall, obtained by endoscopic ultrasound guided microbiopsy procedure. We have used a commercial MUC1 antibody, validated and recommended for diagnostic use, which recognizes fully glycosylated MUC1. Based on the above, we propose a revision of the WHO Classification, specifying that antibodies against tumor associated MUC1 should be used for IPMN subtyping.
Tumor Stroma Interactions, Microenvironment, Inflammatory Response
- The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment
The American journal of pathology 2019 Jan;189(1):44-57
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558722
Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.
- Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma
Gastroenterology 2018 11;155(5):1625-1639.e2
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30092175
BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.
- Inter- and intra-tumoral heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma
The Journal of pathology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30575030
Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- vs. anti-tumoral) in PDAC. We hypothesized that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoral pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoral heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF sub-populations in PDAC. This article is protected by copyright. All rights reserved.
- Epithelial-Stromal Interactions in Pancreatic Cancer
Annual review of physiology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30418798
Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Solid Pseudopapillary Neoplasm
- Prognostic value of progesterone receptor in solid pseudopapillary neoplasm of the pancreas: evaluation of a pooled case series
BMC gastroenterology 2018 Dec;18(1):187
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30547767
BACKGROUND: The role of progesterone receptor (PR) has been reported in a series of pancreatic cysts. However, the relationship between PR and prognosis of solid pseudopapillary neoplasm of the pancreas (SPNP) has not been elucidated so far. The aim of our study was to evaluate the prognostic value of PR in SPNP. METHODS: A total of 76 patients with SPNP treated in our institution from January 2012 to December 2017 were included. Demographic parameters, laboratory data, pathologic information and clinical outcomes were analyzed by the use of survival analysis. In addition, a pooled case series was performed to evaluate the results. RESULTS: The institutional data included 76 patients (17 male and 59 female) ranging from 8 to 90 years (median, 30 years) in age. Kaplan-Meier survival analysis confirmed negative PR result was significantly associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) (both P < 0.001). In the pooled analysis, a total of 62 studies comprising 214 patients with SPNP were included. After multivariable cox analysis, negative PR result remained an independent prognostic factor for SPNP (DFS HR: 14.50, 95% CI: 1.98-106.05, P = 0.008; DSS HR: 9.15, 95% CI: 1.89-44.17, P = 0.006). CONCLUSION: Our results indicated the role of PR in predicting adverse outcome of patients with SPNP and negative PR result may serve as a potential prognostic factor.
- CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas
Virchows Archiv : an international journal of pathology 2019 Jan;474(1):105-109
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30132130
CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.
- Pancreatic Acinar Metaplasia in Distal Esophageal Biopsies Is Associated With Chronic Nonsteroidal Anti-inflammatory Drug Use
Archives of pathology & laboratory medicine 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30525934
CONTEXT.—: The cause of pancreatic acinar metaplasia (PAM) at the distal esophagus/esophagogastric junction is still controversial. Whereas some authors believe it is congenital, others believe it is acquired because of inflammation of the gastric cardia, and more recently it was proposed to be due to chronic proton pump inhibitor use based on a study in rats. OBJECTIVE.—: To determine whether there is correlation between chronic proton pump inhibitor use and PAM in humans. We also investigated the correlation between several clinical and pathologic factors and PAM. DESIGN.—: Four hundred forty-four consecutive biopsies from the distal esophagus/esophagogastric junction were reviewed for the presence of PAM, which was then correlated with several clinical and pathologic findings. RESULTS.—: Pancreatic acinar metaplasia was found in 71 patients (16%). Pancreatic acinar metaplasia was significantly associated with patient age younger than 51 years ( P < .001), chronic carditis ( P = .01), and chronic proton pump inhibitor use ( P = .008). Surprisingly, we also found significant association between PAM and chronic nonsteroidal anti-inflammatory drug use ( P < .001). These associations, including that with chronic nonsteroidal anti-inflammatory drug use, remained significant in multivariate analysis. CONCLUSIONS.—: Our findings confirm the previous reports of significant association between PAM and chronic carditis and the findings from animal studies of association with chronic proton pump inhibitor use. The strong association with chronic nonsteroidal anti-inflammatory drug use has not been previously reported and warrants further studies.
- Tumefactive Inflammatory Diseases of the Pancreas
The American journal of pathology 2019 Jan;189(1):82-93
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558726
Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.
- Clinicopathological and immunological features of follicular pancreatitis-a distinct disease entity characterized by Th17 activation
Histopathology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30515871
AIM: Follicular pancreatitis is a recently recognized, distinct clinicopathological entity characterized by the presence of many intrapancreatic lymphoid follicles with reactive germinal centres. However, the clinicopathological and immunological features and causes have not yet been established. We assessed the clinicopathological and immunological profiles of patients with follicular pancreatitis who underwent surgery. METHODS AND RESULTS: This study included three patients with pancreatic masses (age range: 62-75 years; women:men: 1:2). A histopathological study of the resected pancreatic masses revealed abundant lymphoid follicles with reactive germinal centres in both periductal regions and diffusely within the parenchyma. No storiform fibrosis, obliterative phlebitis, or granulocytic epithelial lesions were observed. The immunohistochemical examination revealed an IgG4/IgG-positive plasma cell ratio <30% in all patients. Podoplanin (Th17 marker)-expressing lymphocytes were present in the lymphoid follicles of those with follicular pancreatitis, whereas these were absent in normal lymph nodes and in lymphoid follicles of those with IgG4-related autoimmune pancreatitis (AIP). An RNA digital counting assay clearly demonstrated that the expression counts of 20 genes, including dendritic cells and lymphoid follicles markers, and related cytokines were significantly higher in follicular pancreatitis than in IgG4-related AIP (p<0.01). The expressions of CCR6 and IL23A, which are genes related to Th17, were high. CONCLUSIONS: This study shows that follicular pancreatitis is a histopathologically and immunologically distinct disease entity of pancreatitis and is characterized by upregulated Th17 expression. This article is protected by copyright. All rights reserved.
- Cholangiolocellular Carcinoma With “Ductal Plate Malformation” Pattern may be Characterized by ARID1A Genetic Alterations
The American journal of surgical pathology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30520820
Cholangiolocellular carcinoma (CLC) is a unique subtype of primary liver carcinoma, which sometimes coexists with hepatocellular carcinoma (HCC), cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). “Ductal plate malformation” (DPM)-pattern of primary liver carcinoma, which resembles biliary lesions in Caroli disease and von Meyenburg complex, is sometimes associated with CLC. We examined genetic alterations of hTERT promoter (hTERT), IDH1 or 2 (IDH1/2), KRAS, ARID1A, PBRM1, ARID2, BAP1, p53 and their association with histologic features such as proportion of CLC and DPM-pattern in 77 patients with primary liver carcinoma diagnosed as cHCC-CCA or CLC. Primary liver carcinomas were histologically subdivided into 29 CLC-predominant (CLC component >80%), 31 with CLC (5% to 80%) and 17 without CLC (<5%). CLC-predominant group was characterized by older age, male-predominant and smaller tumor size. Genetic alterations were detected in hTERT (25%), ARID1A (21%), PBRM1 (20%), ARID2 (3%), BAP1 (1%), p53 (46%), KRAS (5%), and IDH1/2 (8%). ARID1A alteration was more frequent in CLC-predominant group, compared with other groups (P<0.05) and was correlated with the degree of DPM-pattern (P<0.01). Alterations of hTERT and p53 were less frequent in CLC-predominant group compared with “with CLC group” (P<0.05). hTERT mutation was less frequent in carcinomas with DPM-pattern (P<0.01). PBRM1 alteration was more frequent in CLC with focal HCC subgroup and without CLC group compared with other groups (P<0.05). CLC may be a distinct subgroup of primary liver carcinoma, which is different from cHCC-CCA, based on clinicopathologic and genetic alterations. ARID1A alterations may characterize CLC with DPM-pattern and could be a diagnostic immunohistochemical marker for small CLCs with DPM-pattern.
- Data set for the reporting of intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR)
Histopathology 2018 Sep;73(3):369-385
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29573451
Optimal patient management benefits from comprehensive and accurate pathology reports that contribute to cancer staging and prognostication. Proforma reports are used in many countries, but these vary in their structure and implementation. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer the European Society of Pathology and the American Society of Clinical Pathology (ASCP), with the aim of developing an evidence-based reporting data set for each cancer site. It is argued that this should reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of the main malignant liver tumours: intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma and present the ‘required’ and ‘recommended’ elements to be included in the report with an explanatory commentary. This data set incorporates definitions and classifications in the most recent World Health Organisation (WHO) publication on hepatic malignancies (4th edition) and the recently published tumour-node-metastasis (TNM)8 staging system. Widespread adoption and implementation of this data set will enable consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and ultimately result in better patient outcomes.
- Clinical features of isolated proximal-type IgG4-related sclerosing cholangitis
Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30570170
BACKGROUND AND AIMS: IgG4-related sclerosing cholangitis (IgG4-SC) presents as isolated proximal-type sclerosing cholangitis (i-SC). This study sought to clarify the imaging differences between i-SC and Klatskin tumor. The differences between i-SC and IgG4-SC associated with autoimmune pancreatitis (AIP-SC) were also studied. METHODS: Differentiating factors between i-SC and Klatskin tumor were studied. The serum IgG4 level, CA19-9 level, CT findings, cholangiography findings (symmetrical smooth long stricture extending into upper bile duct [SSLS]), endosonographic features (continuous symmetric mucosal lesion to the hilar part [CSML]), endoscopic biopsy results, treatment, relapse, and survival were also compared between patients with i-SC and those with AIP-SC. RESULTS: For a differential diagnosis between i-SC (N = 9) and Klatskin tumor (N = 47), the cutoff value of serum IgG4 level was 150mg/dL (sensitivity=0.857, specificity=0.966). Logistic regression analysis indicated that serum IgG4 level, the presence of SSLS, presence of CSML and the presence of ampulla swollen are independent factor for identifying i-SC. The relapse rate was significantly higher in the IgG4-SC with AIP group than in the i-SC group (log rank, p = 0.046). CONCLUSION: i-SC presents as a nodular lesion with SSLS and/or CSML mimicking a Klatskin tumor. Those endoscopic features might provide a diagnostic clue for i-SC. i-SC is likely to have a more favorable prognosis than IgG4-SC with AIP. This article is protected by copyright. All rights reserved.
Morphology, Diagnostics, IHC
- MUC5B, CA9 and CLDN18 are potential theranostic markers of gallbladder carcinoma
Histopathology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30565710
BACKGROUND: Gallbladder cancer (GBC) is an aggressive tumor usually diagnosed at advanced stages and characterized by a poor prognosis. Using public data of normal human tissues, we found that mRNA and protein levels of MUC5B and CA9 genes are highly enriched in gallbladder tissues. In addition, previous evidence showed that CLDN18 protein expression is higher in GBC. In this study we performed an analysis of these cell surface proteins along the histological progression of GBC in order to identify their theranostic potential. METHODS: Expression of MUC5B, CA9 and CLDN18 was examined by immunohistochemistry in a series of 179 chronic cholecystitis (including 16 metaplastic tissues), 15 dysplasias and 217 GBC samples using tissue microarray analysis. A composite staining score was calculated considering staining intensity and percentage of positive cells. RESULTS: Immunohistochemistry analysis showed a high expression of MUC5B and CA9 among normal epithelium, metaplastic and dysplastic tissues. However, expression of both proteins was observed in about 50% of GBC samples. By contrast, CLDN18 was absent in normal epithelium, but its expression was higher in metaplastic cells. Among GBC cases, approximately half presented high expression of CLDN18. No associations were found between the expression of MUC5B, CA9 and CLDN18 with any clinicopathological features. CONCLUSIONS: CLDN18 is a new metaplasia marker in gallbladder tissues and is conserved in roughly half of GBC cases. MUC5B and CA9 are highly conserved along GBC histological progression. The three markers are potential theranostic markers, in particular CA9 and CLDN18, for which there are already targeted therapies available. This article is protected by copyright. All rights reserved.
- Importance of routine histopathological examination of a gallbladder surgical specimen: Unexpected gallbladder cancer
Journal of cancer research and therapeutics 2018 11;14(6):1325-1329
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30488851
Introduction: Cholecystectomy performed for benign diseases of the gallbladder is important for the diagnosis of gallbladder cancer. This is done by pathological examination of the removed specimens for patients with no detected or suspected complications before surgery. Although some centers undertake selective approaches for histopathological examination of gallbladder specimens, many centers perform this examination routinely. In our study, we investigated results of pathological examinations carried out on cholecystectomy specimens, in respect to unexpected cases of gallbladder cancer. Methods: We reviewed cholecystectomy cases performed for benign diseases of gallbladder from January 2012 to February 2016 by investigating pathological specimens from the gallbladder. We evaluated demographical properties and their association with the pathological diagnosis and frequency of unexpected gallbladder cancer cases. We reported additional treatment and survival information of the malignancy cases after surgery. Results: We reviewed 1294 cases of cholecystectomy, and the mean patient age was 47.5 ± 14.3 years. The most frequent diagnosis was chronic cholecystitis (92.3%), and it was more prevalent among younger patients and female sex (P < 0.0001). Five patients (0.4%) were determined to have gallbladder cancer, and the mean age of these cases was 65.6 ± 18.2 years. Two cases were Stage 2, two cases were Stage 3B, and one case was Stage 3A. There was no T1 or Tis tumor. Conclusion: Routine histopathological examination of gallbladder is significant with respect to the determination of additional interventions at the postoperative period required for cancer cases coincidentally diagnosed.
- Patterns of Presentation, Treatment, and Survival Rates of Gallbladder Cancer: a Prospective Study at a Tertiary Care Centre
Journal of gastrointestinal cancer 2018 Sep;49(3):268-274
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=28367607
BACKGROUND: India has high incidence of gallbladder carcinoma with regional variation in incidence, the highest in Northern India. This study examines the patterns of presentation, treatment strategies, and survival rate of all patients with gallbladder cancer (GBC) evaluated at our tertiary academic hospital over a period of 2 years. METHODS: All patients presented to our institute with established tissue diagnosis of carcinoma gallbladder were accrued in our study over a time period of 2 years. Presentation, treatment modalities, and survival rates were analyzed. RESULTS: One hundred six patients were included: 80 females and 26 males (F: M = 3:1). Median age was 60 years. Eighty patients (75%) had gallstones and 20 patients (21%) had typical history of chronic cholecystitis. The common symptom and sign at presentation were pain in the right upper abdomen (81%) and lump abdomen (49%), respectively. Overall resectability rate was 19.8% (21/106). Eighty-five patients were unresectable or metastatic and treated with palliative intent. Stagewise distribution at diagnosis was stage I (0%), stage II (4%), stage IIIA (10%), stage IIIB (8%), stage IVA (17%), and stage IVB (61%). Estimated 1-year survival for stages II, IIIA, IIIB, IVA, and IVB was 100, 76, 47.4, 26, and 10.6%, respectively. Significant difference in OS was observed among different stages of GBC (p value <0.001). CONCLUSION: If proper investigations are done, radical surgery including multi-organ resection can be curative with acceptable morbidity and mortality. Stage at presentation and ability to perform curative resection are the most important prognostic factors predicting survival. Palliative chemotherapy should be considered for metastatic GBC.
- Systematic review of management of incidental gallbladder cancer after cholecystectomy
The British journal of surgery 2019 Jan;106(1):32-45
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30582640
BACKGROUND: Gallbladder cancer is rare, but cancers detected incidentally after cholecystectomy are increasing. The aim of this study was to review the available data for current best practice for optimal management of incidental gallbladder cancer. METHODS: A systematic PubMed search of the English literature to May 2018 was conducted. RESULTS: The search identified 12 systematic reviews and meta-analyses, in addition to several consensus reports, multi-institutional series and national audits. Some 0·25-0·89 per cent of all cholecystectomy specimens had incidental gallbladder cancer on pathological examination. Most patients were staged with pT2 (about half) or pT1 (about one-third) cancers. Patients with cancers confined to the mucosa (T1a or less) had 5-year survival rates of up to 100 per cent after cholecystectomy alone. For cancers invading the muscle layer of the gallbladder wall (T1b or above), reresection is recommended. The type, extent and timing of reresection remain controversial. Observation time may be used for new cross-sectional imaging with CT and MRI. Perforation at initial surgery had a higher risk of disease dissemination. Gallbladder cancers are PET-avid, and PET may detect residual disease and thus prevent unnecessary surgery. Routine laparoscopic staging before reresection is not warranted for all stages. Risk of peritoneal carcinomatosis increases with each T category. The incidence of port-site metastases is about 10 per cent. Routine resection of port sites has no effect on survival. Adjuvant chemotherapy is poorly documented and probably underused. CONCLUSION: Management of incidental gallbladder cancer continues to evolve, with more refined suggestions for subgroups at risk and a selective approach to reresection.
Gallbladder TNM staging, Margins, Survival
- National Failure of Surgical Staging for T1b Gallbladder Cancer
Annals of surgical oncology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499077
BACKGROUND: Current guidelines recommend radical cholecystectomy with regional lymphadenectomy (RC-RL) for patients with T1b gallbladder cancer (GBC). However, the extent to which these guidelines are followed is unclear. This study aimed to evaluate current surgical practices for T1b GBC and their implications for overall management strategies and associated outcomes. METHODS: This retrospective cohort study investigated patients identified from the National Cancer Data Base (2004-2012) with non-metastatic T1b GBC. The patients were categorized according to type of surgical treatment received: simple cholecystectomy (SC) or RC-RL. Among the patients who had lymph nodes pathologically examined, nodal status was classified as pN- or pN+. Use of any adjuvant therapy was ascertained. Overall survival (OS) was compared based on type of surgical treatment and nodal status. RESULTS: The cohort comprised 464 patients (247 SC and 217 RC-RL cases). The positive margin status did not differ between the two groups (6.1% for SC vs 2.3% for RC-RL; p = 0.128). For RC-RL, the pN+ rate was 15%. Adjuvant therapies were used more frequently in pN+ (53.1% vs 9.4% for pN-). By comparison, 10.9% of the SC patients received adjuvant therapy. The OS for RC-RL-pN- (5-years OS, 64.4%) was significantly better than for RC-RL-pN+ (5-years OS, 15.7%) or SC (5-years OS, 48.3%) (p < 0.001). CONCLUSION: Less than 50% of the patients with a T1b GBC primary tumor undergo the recommended surgical treatment. Given that 15% of these patients have nodal metastasis and in light of the previously described benefits of adjuvant therapy for node positive GBC, failure to perform RC-RL risks incomplete staging and thus undertreatment for patients with T1b GBC.
- Optimal surgical treatment in patients with T1b gallbladder cancer: An international multicenter study
Journal of hepato-biliary-pancreatic sciences 2018 Dec;25(12):533-543
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30562839
BACKGROUND: There is no consensus on the optimal treatment of T1b gallbladder cancer (GBC) due to the lack of evidence and the difficulty of anatomy and pathological standardization. METHODS: A total of 272 patients with T1b GBC who underwent surgical resection at 14 centers with specialized hepatobiliary-pancreatic surgeons and pathologists in Korea, Japan, Chile, and the United States were studied. Clinical outcomes including disease-specific survival (DSS) rates according to the types of surgery were analyzed. RESULTS: After excluding patients, the 237 qualifying patients consisted of 90 men and 147 women. Simple cholecystectomy (SC) was performed in 116 patients (48.9%) and extended cholecystectomy (EC) in 121 patients (51.1%). The overall 5-year DSS was 94.6%, and it was similar between SC and EC patients (93.7% vs. 95.5%, P = 0.496). The 5-year DSS was similar between SC and EC patients in America (82.3% vs. 100.0%, P = 0.249) as well as in Asia (98.6% vs. 95.2%, P = 0.690). The 5-year DSS also did not differ according to lymph node metastasis (P = 0.688) or tumor location (P = 0.474). CONCLUSIONS: SC showed similar clinical outcomes (including recurrence) and survival outcomes as EC; therefore, EC is not needed for the treatment of T1b GBC.
- Positive relationship between number of negative lymph nodes and duration of gallbladder cancer cause-specific survival after surgery
Cancer management and research 2018 12;10():6961-6969
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30588101
Background: Although the prognostic implications of negative lymph nodes (NLNs) has been reported for a variety of tumors, little information has been published about the NLNs in gallbladder cancer (GBC). Patients and methods: In this study, clinicopathological characteristics and survival times of patients who had undergone surgery for GBC were collected from the Surveillance, Epidemiology, and End Results Program-registered TNM stage database and analyzed. Univariate and multivariate Cox proportional hazards models were used to identify the predictors of survival. Results: It was found that a cutoff of one to two NLNs is optimal when assessing the association with survival, survival rates being consistently better with two or more NLNs than with fewer than two. This optimal cutoff value of 2 was identified as an independent prognostic factor by univariate and multivariate analyses (all P<0.001). Specifically, patients with two or more NLNs had better 5-year gallbladder cancer cause-specific survival than those with fewer than NLNs examined for stage I/II, stage III/IV, and all TNM stages (all P<0.001). Conclusion: Our findings indicate that the number of NLNs is an independent prognostic factor after GBC surgery, and, together with the number of positive lymph nodes, this will provide better prognostic information than the number of positive lymph nodes alone.
- External validation of the 8th American Joint Committee on Cancer staging system for gall bladder carcinoma
Journal of gastrointestinal oncology 2018 Dec;9(6):1084-1090
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30603127
Background: To validate the changes within the American Joint Committee on Cancer (AJCC) 8th staging system for gall bladder carcinoma compared to AJCC 7th staging system. Methods: Surveillance, Epidemiology and End Results (SEER) database [2004-2014] was queried. Kaplan-Meier survival analyses and Log-rank testing were assessed according to both AJCC 7th and 8th staging systems. Likewise, Cox cancer-specific hazard ratio was evaluated according to both staging systems. Results: Overall survival was assessed according to the two staging systems; and P values for overall trend (log/rank test) were significant (P<0.001) for both scenarios. Cox regression cancer-specific hazard adjusted for age, gender, histology, gender and surgery was evaluated according to the two staging systems. According to AJCC 7th staging system, the following pair wise hazard ratio comparisons were significant (II vs. IIIA; IIIB vs. IVA; IVA vs. IVB). According to AJCC 8th staging system, the following pair wise hazard ratio comparisons were significant (II vs. IIIA; IVA vs. IVB). C-statistic was assessed using death from gall bladder carcinoma as the dependent variable; and the findings for the two staging systems were as follows: AJCC 7th staging system: 0.684 (SE: 0.008; 95% CI: 0.667-0.701); AJCC 8th staging system: 0.682 (SE: 0.009; 95% CI: 0.665-0.698). Conclusions: There is a comparable discriminatory performance for AJCC 8th staging system compared to AJCC 7th staging system. Change form location-based to number-based N category assessment does not improve the overall prognostic performance of the staging system.
Morphology, Diagnostics, IHC
- Identification of ampullary carcinoma mixed subtype using a panel of six antibodies and its clinical significance
Journal of surgical oncology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30548547
OBJECTIVES: To investigate the function of immunomarkers CK7, CK20, CK17, CDX2, MUC1, and MUC2 in the identification of primary ampullary carcinoma mixed subtype. METHODS: Forty-two cases of primary ampullary carcinoma were performed by immunohistochemical studies. The correlation between the mixed subtype and the other two subtypes and patient survival data was analyzed using the SPSS 16.0 statistical software. RESULTS: Among 42 cases, 12 (28.6%) cases were classified as mixed subtype, which showed variable expression patterns: 91.7% (11/12) for CK7, 83.3% (10/12) for CK20; 66.7% (8/12) for CK17, CDX2, and MUC1; and 50% (6/12) for MUC2. Ten (83.3%) mixed types coexpressed four or more immunomarkers. Eight (19%) intestinal subtypes mainly showed a positive expression of CK20, CDX2, and MUC2. Twenty-two (52.4%) pancreaticobiliary subtypes showed a positive expression of CK7, MUC1, and CK17. Stages III and IV diseases in mixed subtype (25%) and intestinal subtype (25%) were less than pancreaticobiliary subtype(63.6%) (p = 0.039). Follow-up data appeared to show a better survival rate for patients with mixed subtype than those with pancreaticobiliary subtypes. CONCLUSION: Immunohistochemical staining provided a more reliable means of diagnosing mixed ampulla carcinoma. Accurate subtyping of ampullary carcinoma is clinically important to select effective chemotherapy regimens and to assess disease prognosis.
- Distinct immunological properties of the two histological subtypes of adenocarcinoma of the ampulla of Vater
Cancer immunology, immunotherapy : CII 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30604042
Adenocarcinoma of the ampulla of Vater (AOV) is classified into intestinal type (IT) and pancreatobiliary type (PB); however, the immunological properties of these subtypes remain to be characterized. Here, we evaluated the clinical implications of PD-L1 expression and CD8+ T lymphocyte density in adenocarcinomas of the AOV and their potential association with Yes-associated protein (YAP). We analyzed 123 adenocarcinoma-of-the-AOV patients who underwent surgical resection, and tumors were classified into IT or PB type. Tumor or inflammatory cell PD-L1 expression, CD8+ T lymphocyte density in the cancer cell nest (intratumoral) or in the adjacent stroma, and YAP localization and intensity were analyzed using immunohistochemical staining. PB-type tumors showed higher tumoral PD-L1 expression than IT-type tumors, and tumoral PD-L1 expression was associated with a shorter disease-free survival (DFS) [hazard ratio (HR), 1.77; p = 0.045] and overall survival (OS) (HR 1.99; p = 0.030). Intratumoral CD8+ T lymphocyte density was higher in IT type than in PB type and was associated with a favorable DFS (HR 0.47; p = 0.022). The nuclear staining pattern of YAP in tumor cells, compared to non-nuclear staining patterns, was more frequently associated with PB type and increased tumoral PD-L1 expression. Nuclear YAP staining was a significant prognostic factor for OS (HR 2.21; p = 0.022). These results show that the two subtypes of adenocarcinoma of the AOV exhibit significant differences in tumoral PD-L1 expression and intratumoral CD8+ T lymphocyte density, which might contribute to their distinct clinical features.
Ampulla of Vater TNM staging, Margins, Survival
- Histopathologic Predictors of Survival and Recurrence in Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study
Annals of surgery 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30628913
OBJECTIVE: The aim of the study was to define histopathologic characteristics that independently predict overall survival (OS) and disease-free survival (DFS), in patients who underwent resection of an ampullary adenocarcinoma with curative intent. SUMMARY BACKGROUND DATA: A broad range of survival rates have been described for adenocarcinoma of the ampulla of Vater, presumably due to morphological heterogeneity which is a result of the different epitheliums ampullary adenocarcinoma can arise from (intestinal or pancreaticobiliary). Large series with homogenous patient selection are scarce. METHODS: A retrospective multicenter cohort analysis of patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma in 9 European tertiary referral centers between February 2006 and December 2017 was performed. Collected data included demographics, histopathologic details, survival, and recurrence. OS and DFS analyses were performed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Overall, 887 patients were included, with a mean age of 66 ± 10 years. The median OS was 64 months with 1-, 3-, 5-, and 10-year OS rates of 89%, 63%, 52%, and 37%, respectively. Histopathologic subtype, differentiation grade, lymphovascular invasion, perineural invasion, T-stage, N-stage, resection margin, and adjuvant chemotherapy were correlated with OS and DFS. N-stage (HR = 3.30 [2.09-5.21]), perineural invasion (HR = 1.50 [1.01-2.23]), and adjuvant chemotherapy (HR = 0.69 [0.48-0.97]) were independent predictors of OS in multivariable analysis, whereas DFS was only adversely predicted by N-stage (HR = 2.65 [1.65-4.27]). CONCLUSIONS: Independent predictors of OS in resected ampullary cancer were N-stage, perineural invasion, and adjuvant chemotherapy. N-stage was the only predictor of DFS. These findings improve predicting survival and recurrence after resection of ampullary adenocarcinoma.
- Prognostic importance of lymph node ratio after resection of ampullary carcinomas
Journal of gastrointestinal oncology 2018 Dec;9(6):1144-1149
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30603134
Background: The prognosis of the lymph node ratio (LNR) in Vater’s ampulla carcinomas (VACs) is recently studied. However, there are not enough data in several populations like Latin American people. Our aim is to demonstrate the prognosis significance of the LNR in this setting. Methods: Pancreaticoduodenectomies for VACs were identified (n=128) from 1980 through 2015. Based on a ROC curve, a cut-off point of 0.1 was assigned for the LNR and the population was divided into two groups for comparison. Results: The LNR ≥0.1 group was statistically significant associated with recurrence (38.5% vs. 19.5%), pT3-T4 tumors (69.2% vs. 29.3%), poorly differentiated tumors (46.2% vs. 17.5%), lymphovascular invasion (61.5 vs. 17.1%), perineural invasion (38.5% vs. 19.5%), and positive margins (15.4% vs. 2.4%). In the multivariate analysis, LNR (HR 2.891; CI: 1.987-3.458, P=0.02), LNM (HR 2.945; CI: 2.478-3.245, P=0.002), perineural invasion (HR 3.327; CI: 3.172-4.156, P=0.003), and recurrence (HR 3.490; CI: 2.896-4.122, P=0.001) were associated with lower survival. Conclusions: The LNR is a good predictor of survival and worse oncological outcomes for VACs after resection.
PanNET, Pancreatic Neuroendocrine Tumors and related neuroendocrine neoplasms
- Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30497875
BACKGROUND/OBJECTIVES: The biological features of cystic pancreatic neuroendocrine tumors (PNETs) remain unclear. The aim of this study was to clarify the clinicopathological characteristics of non-functioning PNETs (NF-PNETs) with a cystic component. METHODS: The medical records of 75 patients with NF-PNETs who had undergone resection in our institution were retrospectively reviewed. Clinicopathological factors were compared between PNETs with and without a cystic component. Expression of somatostatin 2 receptor (SSTR-2) was also analyzed. RESULTS: Cystic PNETs were diagnosed in 14 patients (19%). The proportion of men was significantly higher for cystic than solid PNETs (79% vs. 44%, P < 0.05) and cystic PNETs were significantly larger than solid PNETs (25 mm vs. 17 mm, P < 0.01). However, there were no significant differences in the prevalence of lymph node metastases (14% vs. 10%, P = 0.64), hepatic metastasis (7% vs. 3%, P = 0.54), or disease-free survival rate (both 86%, P = 0.29) between PNETs with and without a cystic component. SSTR-2 expression was more frequently observed in PNETs with a cystic component than in those without (100% vs. 70%, P < 0.01). CONCLUSIONS: Although cystic PNETs were larger upon diagnosis than solid PNETs in this study, prognosis after surgical resection did not differ significantly between these types of PNET. Somatostatin receptor scintigraphy and somatostatin analogues may be more useful for diagnosing and treating cystic PNETs, respectively.
- Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d’étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne)
Annals of surgery 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30585820
OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d’étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.
- In Situ Hybridization Analysis of Long Non-coding RNAs MALAT1 and HOTAIR in Gastroenteropancreatic Neuroendocrine Neoplasms
Endocrine pathology 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30600442
Recent studies suggest onco-regulatory roles for two long non-coding RNAs (lncRNAs), MALAT1 and HOTAIR, in various malignancies; however, these lncRNAs have not been previously examined in neuroendocrine neoplasms (NENs) of gastroenteropancreatic origins (GEP-NENs). In this study, we evaluated the expressions and prognostic significance of MALAT1 and HOTAIR in 83 cases of GEP-NENs (60 grade 1, 17 grade 2, and 6 grade 3 tumors) diagnosed during the years 2005-2017. Expression levels of MALAT1 and HOTAIR were digitally quantitated in assembled tissue microarray slides labeled by chromogenic in situ hybridization (ISH) using InForm 1.4.0 software. We found diffuse nuclear expression of both HOTAIR and MALAT1 in all primary tumors of GEP-NENs with variable intensities. By multivariate model which adjusted for age and histologic grade, high expression of HOTAIR was associated with lower presenting T and M stages and subsequent development of metastases (P < 0.05). MALAT1 expression was associated with presenting T stage and development of metastases (P < 0.05). In summary, MALAT1 and HOTAIR are commonly expressed in GEP-NENs. High expression of either lncRNA showed grade-independent associations with clinically less aggressive disease.
- Touch imprint cytology on endoscopic ultrasound fine-needle biopsy provides comparable sample quality and diagnostic yield to standard eus-fna specimens in the evaluation of solid pancreatic lesions
Cytopathology : official journal of the British Society for Clinical Cytology 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30484917
OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the gold standard for the diagnosis of solid pancreatic lesions (SPLs). Cytological samples can also be obtained using touch imprint cytology (TIC) on EUS fine-needle biopsy (FNB) specimens. We aimed to compare sample quality and diagnostic yield of EUS-FNA-standard cytology (EUS-FNA-SC) to that of EUS-FNB-TIC in a series of patients with SPLs. METHODS: Thirty-two consecutive patients referred for EUS-tissue acquisition of SPLs who underwent rapid on-site evaluation (ROSE) of both EUS-FNA-SC and paired EUS-FNB-TIC during the same endoscopic session were retrospectively identified. Sample quality (evaluated in terms of blood contamination, presence of clots, tissue casts, cellularity, and necrosis) and diagnostic yield were compared between the techniques. RESULTS: The mean number of passes to reach diagnosis at ROSE was similar between EUS-FNA-SC and EUS-FNB-TIC (1.09 ± 0.3 vs 1.13 ± 0.34, P = .711). EUS-FNA-SC scores of sample quality were comparable to those of EUS-FNB-TIC (blood contamination, 2.47 ± 1.11 vs 2.25 ± 1.14, P = .109; clots, 1.25 ± 0.76 vs 1.19 ± 0.69, P = .624; tissue casts, 3.56 ± 0.88 vs 3.59 ± 1.09, P = .872; cellularity, 2.84 ± 1.11 vs 3.09 ± 1.09, P = .244; necrosis, 2.25 ± 1.08 vs 2.53 ± 1.02 P = .059; total score, 12.38 ± 2.88 vs 17.66 ± 2.38, P = .536). Adequacy, sensitivity and diagnostic accuracy of the two sampling techniques were equal (93.7%, 90.6%, 90.6%, respectively). CONCLUSIONS: EUS-FNB-TIC provides comparable samples to those of EUS-FNA-SC and combines the benefits of cytology and histology for the evaluation of SPLs by employing a single needle during the same endoscopic procedure. This article is protected by copyright. All rights reserved.
- Diagnostic Value of S100p, IMP3, Maspin, and pVHL in the Differantial Diagnosis of Pancreatic Ductal Adenocarcinoma and Normal/chronic Pancreatitis in Fine Needle Aspiration Biopsy
Journal of cytology 2018 12;35(4):247-251
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30498299
Introduction: Differentiation between pancreatic ductal adenocarcinoma (PDAC) from benign mimickers is a well-known problem in cytological materials. Recent studies incorporated biological markers into this question and some studies showed that expression of S100P, IMP3, and maspin as well as nonexpression of von Hippel-Lindau gene product (pVHL) were significantly correlated with PDAC. In this study, we aimed to investigate diagnostic value of maspin, IMP3, S100P, and pVHL immunostaining in fine needle aspiration biopsies (FNABs) of pancreatic lesions. Materials and Method: In all, 33 cases of FNAB cell blocks of PDAC and 34 cases of surgical non-neoplastic pancreas specimens which were retrieved from the archives slides from 2007 to 2011 were included in this study. All the cases were stained with maspin, IMP3, S100P, and pVHL. Expression patterns of markers were scored and compared with benign mimickers. Test performance of each antibody and possible antibody combinations were also evaluated. Results: The study was composed of 33 PDAC and 34 control cases (8 chronic pancreatitis, 3 mucinous cystic neoplasm, and 23 nontumoral pancreatic tissue of PDAC). Diagnostic sensitivity for malignancy in S100P, IMP3, and maspin was 84.8%, 81.8%, and 87.5%, respectively. Specificity of these three markers was 100%. Sensitivity and specificity of pVHL for detecting nontumoral pancreatic tissue were 100% and 81.8%, respectively. When maspin, IMP3, and S100P expression were used together as triple test, sensitivity was 62.5% and specificity 100%. However, when any two of each three markers were evaluated (triple test/dual response), sensitivity reached 93.8% and specificity 100%. Conclusion: We observed that dual response in triple test (positive staining with two of these three markers) of maspin, IMP3, and S100P immunocytochemistry is very sensitive and specific in differential diagnosis of PDA and non-neoplastic pancreatic lesions. pVHL may have an additional role, when triple assessment is not satisfactory.
- Pleomorphic and atypical multinucleated giant cells in solid pseudopapillary neoplasm of pancreas: A diagnostic pitfall in cytology and a review of the literature
Diagnostic cytopathology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30552752
Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low-grade malignancy typically occurring in young women. Occasionally, these neoplasms present with pleomorphic to atypical multinucleated giant tumor cells which may mimic high-grade malignancy. Our patient is a 25-year-old male who presented with one year of intermittent epigastric pain. Magnetic resonance imaging showed a 3.1 × 2.5 cm mass in the pancreas body. Endoscopic ultrasound-guided fine needle aspiration of the mass showed large pleomorphic cells and atypical multinucleated giant cells in a background of singly scattered polygonal cells. Focally, these cells surrounded delicate hyalinized to fibrovascular cores forming pseudopapillae. Immunohistochemical stains show tumor cells are positive for beta-catenin, CD10, vimentin, and CD56. Although rare surgical pathology publications have described the presence of pleomorphic to atypical multinucleated giant cells occurring in SPN, to our knowledge, this is the first case reported example focused on cytomorphologic illustration and description.
- Cytopathological results of initial endoscopic ultrasound-guided fine needle aspiration for primary mass and prognosis in pancreatic cancer patients
Cytopathology : official journal of the British Society for Clinical Cytology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30570774
OBJECTIVES: Clinical outcomes remain unclear in patients suspected of having pancreatic cancer with indeterminate endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) results. This work aimed to investigate the prognosis of pancreatic cancer patients with indeterminate findings at initial EUS-FNA. METHODS: Findings in all patients who underwent EUS-FNA for suspected pancreatic cancer between 2008 and 2015 at the National Cancer Center, Korea, were retrospectively reviewed. A final diagnosis of pancreatic ductal adenocarcinoma was based on pathology reports. RESULTS: Of the 144 patients evaluated, 113 (78%) were diagnosed as being positive/suspicious for malignancy on cytological evaluation, and 31 (22%) as having atypia/negative/non-diagnostic findings at initial EUS-FNA but subsequently diagnosed with pancreatic ductal adenocarcinoma. Tumor size, clinical stage and treatment modalities did not differ significantly between these two groups. Median overall survival was significantly shorter in patients diagnosed (11.3 ± 0.74 months; 95% confidence interval [CI], 9.4-12.8 months) than non-diagnosed (16.9 ± 2.34 months; 95% CI, 12.0-17.4 months) on initial EUS-FNA (P=0.024). Multivariate Cox regression analysis showed that a non-diagnosis on initial EUS-FNA was independently associated with better overall survival (hazard ratio, 0.58; 95% CI, 0.38-0.88; P=0.011). CONCLUSIONS: Non-diagnostic results on initial EUS-FNA of a primary mass may be associated with better prognosis in patients with pancreatic cancer. . This article is protected by copyright. All rights reserved.
- Factors Associated with Malignant Biliary Strictures in Patients with Atypical or Suspicious Cells on Brush Cytology
Clinical endoscopy 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30625267
Background/Aims: Pathological diagnosis of biliary strictures with atypical or suspicious cells on endoscopic retrograde brush cytology and indeterminate strictures on imaging is challenging. The aim of this study was to identify markers for malignant strictures in such cases. Methods: We retrospectively analyzed data collected from 146 consecutive patients with indeterminate biliary strictures on imaging who underwent endoscopic retrograde brush cytology from 2007 to 2013. Factors associated with malignant strictures in patients with atypical or suspicious cells on brush cytology were identified. Results: Among the 67 patients with a malignant disease (48 cholangiocarcinoma, 6 gallbladder cancer, 5 pancreatic cancer, 5 ampulla of Vater cancer, and 3 other types), 36 (53.7%) had atypical or suspicious cells on brush cytology. Among these, the factors that independently correlated with malignant strictures were stricture length (odds ratio [OR], 5.259; 95% confidence interval [CI], 1.802- 15.294) and elevated carbohydrate antigen 19-9 (CA19-9) (OR, 3.492; 95% CI, 1.242-9.815), carcinoembryonic antigen (CEA) (OR, 4.909; 95% CI, 1.694-14.224), alkaline phosphatase (ALP) (OR, 3.362; 95% CI, 1.207-9.361), and gamma-glutamyl transpeptidase (rGT) (OR, 4.318; 95% CI, 1.512-12.262). Conclusions: Elevated levels of CA19-9, CEA, ALP, and rGT and stricture length are associated with malignant strictures in patients with indeterminate biliary strictures on imaging and atypical or suspicious cells on brush cytology.
- Advances in the cytologic diagnosis of gastroenteropancreatic neuroendocrine neoplasms
Cancer cytopathology 2018 Dec;126(12):980-991
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30485690
Two-thirds of neuroendocrine neoplasms arising in the human body originate from the gastrointestinal system or pancreas. Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous, comprising both well differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The clinical presentation, molecular characteristics, and behavior are distinct for NETs and NECs. Fine-needle aspiration is an important modality for the primary diagnosis and staging of these neoplasms and can provide information of prognostic and therapeutic significance. Our evolving understanding of neuroendocrine neoplasm biology has led to several iterations of classification. In this review, new concepts and issues most relevant to cytology diagnosis of gastroenteropancreatic neuroendocrine neoplasms are discussed, such as newer detection methods that aid in diagnosis and staging, recent changes in World Health Organization classification, practical issues related to grading these neoplasms on cytology, guidelines for diagnostic reporting, and panels of immunohistochemical stains for the diagnosis of metastasis. The current understanding of genetic and epigenetic events related to tumor development and potential applications for cytology also are presented as they relate to prognostication and recent therapeutic advances.
- miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma
The American journal of pathology 2019 Jan;189(1):58-70
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558723
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3’-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
- Mechanosignalling via integrins directs fate decisions of pancreatic progenitors
Nature 2018 12;564(7734):114-118
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30487608
The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells1. Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions1,2. Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin α5 as the extracellular cue that cell-autonomously, via the F-actin-YAP1-Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM-integrin α5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas.
- Identification of Key Potential Targets and Pathway for Arsenic Trioxide by Systemic Bioinformatics Analysis in Pancreatic Cancer
Pathology oncology research : POR 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30506130
Arsenic trioxide is an approved chemotheraputic agent for the treatment of acute promyelocytic leukemia (APL). Recently, numerous studies suggested that arsenic trioxide acts as anti-cancer roles in various human malignancies. However, the molecular mechanisms are not fully elucidated. In this study, we explored the critical targets of arsenic trioxide and their interaction network systematically by searching the publicly available published database like DrugBank (DB) and STRING. Seven direct protein targets (DPTs) and 111 DPT-associated genes were identified. The enrichment analysis of arsenic trioxide associated genes/proteins revealed 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Among these pathways, phosphatidylinositol-4,5-bisphosphate-3-kinase -Akt (PI3K-Akt) single pathway and pancreatic cancer pathway are highly correlated with arsenic trioxide and have 5 overlapped targets. Then we investigated the gene alternation of selected critical genes in pancreatic cancer studies using cBio portal. These results indicated that arsenic trioxide could act anti-tumor function through PI3K-Akt single pathway and identified critical genes might be therapeutic targets for pancreatic cancer.
- Is mitochondrial DNA copy number a good prognostic marker in resectable pancreatic cancer?
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30528645
BACKGROUND: The aim of this prospective study was to investigate mitochondrial DNA (mtDNA) copy number in a group of resectable pancreatic cancer (PC) tumor tissues and adjacent normal pancreatic tissues, and to explore the correlation between the mtDNA content in tissues and the clinicopathological parameters and the overall survival. METHODS: Relative mtDNA copy number was measured by the quantitative PCR-based assay. The tumors specimens (n = 43) originated from the patients with pathologically confirmed pancreatic ductal adenocarcinoma who did not receive any neoadjuvant systemic therapy. The adjacent normal pancreatic tissue samples (n = 31) were obtained from surgical margins. RESULTS: mtDNA copy number was significantly lower in PC tissue (P < 0.001) compared to adjacent normal pancreatic tissue. Jonckheere-Terpstra trend testing indicated a statistically significant decrease in median mtDNA copy number across the differentiation (adjacent normal pancreatic tissue, low-grade, intermediate-grade, high-grade cancer), P < 0.001. However, the survival analyses failed to show a significant difference in survival between patients with high and low mtDNA copy number. CONCLUSIONS: To the best of our knowledge, we provided the first evidence that mitochondrial DNA copy number was significantly lower in pancreatic cancer tissue (P < 0.001) compared to adjacent normal pancreatic tissue. Also, we demonstrated that mitochondrial copy number was not a significant marker for predicting prognosis in resectable pancreatic cancer.
- Sonic Hedgehog Protein is Frequently Up-Regulated in Pancreatic Cancer Compared to Colorectal Cancer
Pathology oncology research : POR 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30539521
Sonic hedgehog (SHH) is a secreted protein which functions in autocrine or paracrine fashion on target cells to activate hedgehog (HH) signalling cascade responsible for growth and proliferation. This study is an attempt to understand the expression dynamics of SHH protein in colon, rectal and pancreatic cancers. Protein expression of SHH was studied by Western Blotting in the histologically confirmed colon, rectum and pancreatic cancer tissue samples along with their adjacent normal tissues. Only 31.4% (11 of 35) and 26.9% (7 of 26) of colon and rectal cancer cases respectively showed an increase in SHH expression in tumours compared to 72.7% (24 of 33) of the pancreatic cancer cases when compared with their adjacent normal tissues. Our results suggest that SHH may have a strong role in the predisposition of Pancreatic cancer and could possibly be used as a diagnostic or prognostic biomarker.
- Higher notch expression implies poor survival in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;18(8):954-961
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30297095
BACKGROUND: At present, pancreatic ductal adenocarcinoma (PDAC) is a fetal disease lack of effective prognostic and therapeutic methods resulting in high mortality. The Notch signaling has been demonstrated being up- or down-regulated in many cancers, but the effects in pancreatic ductal adenocarcinoma are still controversial. Moreover, the available cases in an individual study are of small samples. Therefore, it is essential to define the effect of Notch signaling in pancreatic ductal adenocarcinoma with larger samples. METHODS: Conducted from 6 eligible studies and 463 pancreatic ductal adenocarcinoma patients, this was the first meta-analysis to analyze the correlation between the Notch signal pathway and pancreatic ductal adenocarcinoma. All data were sourced from The National Center for Biotechnology Information, Web of Science and Cochrane. The articles which matched the inclusion criteria were included. All included data were analyzed and performed by Review Manager 5.3. RESULTS: The results indicated that high expression of Notch signaling proteins was associated with poor overall survival of pancreatic ductal adenocarcinoma patients (pooled hazard ratio>2.00; P < 0.001). Moreover, poor survival was related to high expression of Notch3 (pooled hazard ratio: 2.05; confidence interval: 1.49-2.82; P < 0.001) and DLL4 (pooled hazard ratio: 2.13; confidence interval: 1.37-3.32; P < 0.001). CONCLUSIONS: This meta-analysis supports that Notch signaling proteins may be available as prognostic factors for pancreatic ductal adenocarcinoma progression and patient survival. Higher expression of Notch signaling proteins indicated poor survival of pancreatic ductal adenocarcinoma patients. Targeting Notch signaling components, especially Notch3 protein, would be beneficial for therapies.
- ALKBH5 gene is a novel biomarker that predicts the prognosis of pancreatic cancer: A retrospective multicohort study
Annals of hepato-biliary-pancreatic surgery 2018 Nov;22(4):305-309
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30588520
Backgrounds/Aims: Discovery of new prognostic factors for cases in which the pancreatic cancer scoring and staging system does not result in a clear definition is imperative. We examined the role of Human AlkB homolog H5 (ALKBH5) as a prognostic marker for pancreatic cancer. Methods: Patient data were extracted from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). The prognostic value of ALKBH5 was confirmed via analysis of ALKBH5 and other clinical factors, such as age, sex, and stage, using the time-dependent area under the curve (AUC) of Uno’s C-index, the AUC value of the receiver operating characteristics (ROC) at three years, the Kaplan-Meier survival curve, and multivariate analysis. Results: ALKBH5 showed excellent prognosis prediction in comparison with existing markers in the two independent cohorts (n=262). Kaplan-Meier survival analysis showed that ALKBH5 expression was positively associated with overall survival (log-rank test, ICGC, p=0.001; TCGA, p=0.01). Notably, comparison of C-index and AUC values in ROC analysis showed that ALKBH5 was associated with high C-index and AUC values compared with other clinical variables (C-index: ICGC, 0.621; TCGA, 0.614 and AUC at three years: ICGC, 0.609; TCGA, 0.558). Multivariate analysis demonstrated thatALKBH5 is an independent prognostic factor (ICGC, p=0.0123; TCGA, p<0.001). Conclusions: These findings contribute to the study of RNA methylation in pancreatic cancer. We believe that ALKBH5 is a new prognostic marker for pancreatic cancer.
- Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
Journal of the National Cancer Institute 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30541042
Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
- High Expression of Long Noncoding RNA HOTAIRM1 is Associated with the Proliferation and Migration in Pancreatic Ductal Adenocarcinoma
Pathology oncology research : POR 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30613920
Pancreatic ductal adenocarcinoma (PDAC) is an incurable malignancy. Long noncoding RNA (LncRNA) HOTAIRM1 (HOX antisense intergenic RNA myeloid 1) has been shown to play important roles in the progression of several type cancers. However, the exact role of HOTAIRM1 in PDAC development remains largely unknown. This study aims to evaluate the potential function of HOTAIRM1 in the development and progress of PDAC. HOTAIRM1 expression was measured by RT-qPCR in forty seven paired human PDAC tissues and five PDAC cell lines. SW1990 and PANC-1 cells were transfected with siHOTAIRM1 to achieve HOTAIRM1 silence. MTT assay and colony formation assay were used to detect the effect of HOTAIRM1 knockdown on cell proliferation. The impact of HOTAIRM1 silence on cell cycle and apoptosis was assessed by flow cytometry assay. Transwell migration assay was performed to explore the influence of HOTAIRM1 downregulation on the migratory potential of PDAC cells. Western blot assay was applied to determine the expression changes of cell cycle, apoptosis, and migration-related genes before and after downregulating HOTAIRM1. HOTAIRM1 expression was abnormally upregulated in PDAC tissues and cells when compared with the control samples, and was positively associated with the expression of KRAS gene mutation. In vitro functional experiments, HOTAIRM1 expression was significantly downregulated by transfection with siHOTAIRM1 in SW1990 and PANC cell lines. HOTAIRM1 knockdown attenuated cell proliferation by inducing cell cycle arrest at G0/G1 phase, promoted cell apoptosis, and inhibited cell migration in PDAC cells by regulating related-genes expression. In conclusion, HOTAIRM1 plays a critical role in PDAC progression, which may be a novel diagnostic and rational therapeutic target for the treatment of pancreatic ductal adenocarcinoma.
- Genomic Landscape of Pancreatic Adenocarcinoma in Younger vs Older Patients: Does Age Matter?
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30617137
PURPOSE: State-of the art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine if early-onset PDAC (EOPC; ≤ 55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥ 70 years). EXPERIMENTAL DESIGN: Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering (MSK) were consented for MSK-IMPACT next generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression and protein expression. The third dataset was an Australian cohort of PDAC. Clinical data were correlated with genomic analyses. RESULTS: Two hundred and ninety-three samples were analyzed, yielding 90 patients (pts) aged ≤ 55 years and 203 pts aged ≥ 70 years. Among the genes known to be associated with carcinogenesis SMAD4 displayed higher mutation rates in younger patients. Comprehensive transcriptomic analysis of cellular pathways indicated that the TGFb pathway has increased activation and the expression levels of phospo-GSK3 were higher in EOPC. Survival outcomes revealed no differences between age groups. CONCLUSIONS: These exploratory analyses suggest that there may be somatic gene alterations within the population of early onset PDAC patients that involve unique cellular pathways compared with average onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future evaluation to extend these observations.
- Epithelial plasticity is crucial for pancreatic cancer metastatic organotropism
Annals of translational medicine 2018 Nov;6(Suppl 1):S53
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30613628
- Rab14 overexpression regulates gemcitabine sensitivity through regulation of Bcl-2 and mitochondrial function in pancreatic cancer
Virchows Archiv : an international journal of pathology 2018 Sep;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30267303
Rab family protein Rab14 has been implicated in the development of human cancers. To date, its expression pattern, biological function, and potential mechanism in pancreatic cancer have not been explored. In this study, we analyzed Rab14 expression in 103 cases of pancreatic cancer tissues using immunohistochemistry (IHC) and found that Rab14 was overexpressed in 41/103 cases (39.8%). Rab14 overexpression correlated with the advanced stage. Moreover, elevated Rab14 levels indicated poor prognosis of patients with pancreatic cancers. We used BxPC-3 and Capan-2 respectively for plasmid and siRNA transfection. MTT and colony formation assays showed that Rab14 transfection increased cell proliferation and colony formation in BxPC-3 cells. Rab14 siRNA knockdown inhibits proliferation and colony formation ability in Capan-2 cell line. Cell cycle analysis showed that Rab14 facilitated cell cycle progression. Matrigel invasion assay showed that Rab14 promoted BxPC-3 cell invasion while its depletion inhibited Capan-2 cell invasion. In addition, MTT and AnnexinV/PI analysis demonstrated that overexpression of Rab14 reduced gemcitabine sensitivity which conversely was increased by Rab14 knockdown. We also demonstrated that Rab14 upregulated mitochondrial membrane potential (MMP) while its depletion downregulated MMP during gemcitabine treatment. In addition, western blotting revealed that Rab14 overexpression upregulated cyclin D1, cyclin A, cyclin E, p-Rb, and Bcl-2 and downregulated p21. Rab14 also downregulated caspase3, PARP cleavage, and cytochrome c release. In conclusion, our data indicated that Rab14 was overexpressed in pancreatic cancer and promotes growth and gemcitabine resistance, possibly through regulation of mitochondrial function and Bcl-2.
Molecular Studies on Pancreatitis & Other Diseases
- Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30583980
BACKGROUND: Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown. METHODS: To uncover the role of TLR3 signaling in acute pancreatitis, we induced a cerulein-mediated pancreatitis in Tlr3 and Ticam1 knockout (KO) mice and in wildtype animals. The exocrine damage was determined by blood serum analysis and histological examination. Immunohistochemistry, gene expression and immunoblot analysis were conducted to study TLR3 function. RESULTS: After the induction of an acute pancreatitis, wildtype mice showed a high endosomal TLR3 expression in acinar cells. In comparison to wildtype and Ticam1 KO mice, Tlr3 KO mice exhibited the highest severity of pancreatitis with an increased NF-κB activation and elevated expression of the pro-inflammatory cytokines Il6 and Tnf, although the amount of infiltrating immune cells was unaffected. Additionally, we detected a strong elevation of acinar cell necrosis and reduced levels of cleaved caspase 8 in Tlr3 and Ticam1 KO mice. CONCLUSIONS: TLR3 and its downstream adaptor TICAM1 are important mediators of acinar cell damage in acute pancreatitis. They possess a critical role in programmed cell death and our data suggest that TLR3 signaling controls the onset and severity of acute pancreatitis.
Tumor Stroma Interactions, Microenvironment, Inflammatory Response, Microbiome
- Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features
Gastroenterology 2018 12;155(6):1999-2013.e3
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30165049
BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.
- Refining Classification of Pancreatic Cancer Subtypes to Improve Clinical Care
Gastroenterology 2018 12;155(6):1689-1691
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30419209
- Increase of Tumor Infiltrating γδ T-cells in Pancreatic Ductal Adenocarcinoma Through Remodeling of the Extracellular Matrix by a Hyaluronan Synthesis Suppressor, 4-Methylumbelliferone
Pancreas 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30589828
OBJECTIVES: Desmoplastic changes of extracellular matrix (ECM) containing large amounts of hyaluronan (HA) are of interest in chemo- and immunoresistance of pancreatic ductal adenocarcinoma (PDAC). The goal of this study was to evaluate the effects of 4-methylumbelliferone (MU), a selective inhibitor of HA, on ECM and to examine how MU affects adoptive immunotherapy. METHODS: The effect of MU on cell proliferation, HA synthesis and formation of ECM were investigated in four PDAC cell lines. In addition, the cytotoxicity of γδ T-cell-rich peripheral blood mononuclear cells (PBMCs) collected from healthy donors and stimulated with zoledronate and interleukin-2 was examined in the presence of MU. The amount of HA and tumor-infiltrating lymphocytes were also investigated in mice xenograft models. RESULTS: In vitro, 1.0 mM MU inhibited cell proliferation by 45-70% and HA synthesis by 55-80% in all four PDAC cell lines, and enhanced γδ T-cell-rich PBMC-mediated cytotoxicity against PDAC cells. In vivo, MU reduced intratumoral HA and promoted infiltration of inoculated γδ T-cells into tumor tissue, and consequently suppressed tumor growth. CONCLUSIONS: 4-methylumbelliferone may be an effective immunosensitizer against PDAC through induction of structural changes in the ECM.
- Evaluating the Regulatory Immunomodulation Effect of Irreversible Electroporation (IRE) in Pancreatic Adenocarcinoma
Annals of surgical oncology 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30610562
BACKGROUND: Irreversible electroporation (IRE) has been demonstrated as an effective local method for locally advanced (stage 3) pancreatic adenocarcinoma. Immune regulatory T cells (Tregs) induce immunosuppression of tumors by inhibiting patients’ anti-tumor adaptive immune response. This study aimed to evaluate the immunomodulation effect of IRE to identify an ideal time point for potential adjuvant immunotherapy. METHODS: This study prospectively evaluated an institutional review board-approved study of patients undergoing either in situ IRE or pancreatectomy. Patient blood samples were collected at different time points (before surgery [preOP] and on postoperative day [POD] 1, POD3, and POD5). Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for three different CD4 + Treg subsets (CD25 + CD4 +, CD4 + CD25 + FoxP3 +, CD4 + CD25 + FoxP3 -) by flow cytometry and analyzed for median fold change (MFC) between each two consecutive time points (MFC = log2(T2/T1)). RESULTS: The study analyzed 15 patients with in situ IRE (n = 11) or pancreatectomy (PAN) (n = 4). In both groups, CD25 + CD4 + Tregs decreased on POD1 followed by a steady increase in pancreatectomy, whereas the trend in the IRE group reversed between D3 and D5 (MFC: IRE [- 0.01], PAN [+ 0.39]). For each period, CD4 + CD25 + FoxP3 + Tregs showed the most dramatic inverse effect, with D3 to D5 showing the most change (MFC: IRE [- 0.18], PAN [+ 0.39]). Also, CD4 + CD25 + FoxP3 - Tregs showed an inverse effect between D3 and D5 (MFC: IRE [- 0.25], PAN [+ 0.49]). Altogether, the Treg trend was inversely affected by the in situ IRE procedure, with the greatest cumulative significant change for all three Treg subsets between D3 and D5 (MFC ± SEM: IRE [- 0.24 ± 0.05], PAN [+ 0.37 ± 0.02]; p = 0.016). CONCLUSIONS: The study data suggest that in situ IRE procedure-mediated Treg attenuation between POD3 and POD5 can provide a clinical window of opportunity for potentiating clinical efficacy in combination with immunotherapy.
- Functions of the CXC ligand family in the pancreatic tumor microenvironment
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Oct;18(7):705-716
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30078614
Therapeutic resistance is the major contributor to the poor prognosis of and low survival from pancreatic cancer (PC). Cancer progression is a complex process reliant on interactions between the tumor and the tumor microenvironment (TME). Members of the CXCL family of chemokines are present in the pancreatic TME and seem to play a vital role in regulating PC progression. As pancreatic tumors interact with the TME and with PC stem cells (CSCs), determining the roles of specific members of the CXCL family is vital to the development of improved therapies. This review highlights the roles of selected CXCLs in the interactions between pancreatic tumor and its stroma, and in CSC phenotypes, which can be used to identify potential treatment targets.
- Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer
Proceedings of the National Academy of Sciences of the United States of America 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30635425
Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.
Molecular Pathology Preneoplastic and Preinvasive Lesions, PanIN, IPMN, MCN, ICPN
- Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion
Cancer letters 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30590101
The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.
- DLEC1 methylation is associated with a better clinical outcome in patients with intrahepatic cholangiocarcinoma of the small duct subtype
Virchows Archiv : an international journal of pathology 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30610381
Intrahepatic cholangiocarcinoma is a complex disease with three different histologic subtypes, the large duct, small duct, and bile ductular types. In the present study, we elucidated whether the three histological subtypes have differences in their methylation profiles and developed a DNA methylation marker that might help identify a subset of ICC with a different prognosis. We screened 113 promoter CpG island loci against 10 cases of intrahepatic cholangiocarcinoma and normal cystic ducts using the MethyLight assay and selected 30 CpG island loci with cancer-associated hypermethylation. Then, we analyzed 172 intrahepatic cholangiocarcinomas for the methylation state at these 30 loci. Six loci, including DLEC1, were more frequently methylated in the bile ductular type and small duct type, whereas six loci were more frequently methylated in the large duct type. Of these 30 loci, DLEC1 methylation was found mainly in the bile ductular type and small duct type but rarely in the large duct type. DLEC1 methylation was significantly associated with a better clinical outcome in intrahepatic cholangiocarcinomas of the small duct type but not of the bile ductular type. DLEC1 methylation was an independent prognostic variable in both cancer-specific survival and recurrence-free survival. For patients with intrahepatic cholangiocarcinoma of the small duct type (n = 68), DLEC1 methylation was found in 26 (38.2%) and was associated with a better clinical outcome for both cancer-specific survival and recurrence-free survival. Our findings suggest that DLEC1 methylation can be utilized to identify a subset with a better prognosis in intrahepatic cholangiocarcinomas of the small duct type.
- EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma
Virchows Archiv : an international journal of pathology 2019 Jan;474(1):39-46
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30349952
Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.
- Prognostic role of BAP-1 and PBRM-1 expression in intrahepatic cholangiocarcinoma
Virchows Archiv : an international journal of pathology 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30377796
Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.
- MiR-1-5p is down-regulated in gallbladder carcinoma and suppresses cell proliferation, migration and invasion by targeting Notch2
Pathology, research and practice 2018 Oct;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30497876
BACKGROUND: Numerous studies have demonstrated that aberrant microRNAs (miRNAs) are involved in tumorigenesis and tumor progression. Nevertheless, the precise role of miR-1-5p in gallbladder carcinoma cell growth and metastasis remains not fully revealed. MATERIAL AND METHODS: The levels of miR-1-5p were detected in gallbladder carcinoma tissues and cell lines using qRT-PCR method. A series of functional assays, including cell proliferation, colony formation, wound healing and Transwell invasion were conducted using miR-1-5p or miR-1-5p inhibitor transfected cells. RESULTS: MiR-1-5p was remarkably down-regulated in gallbladder carcinoma tissues and cell lines compared to normal. In addition, over-expression of miR-1-5p markedly suppressed the growth, migration and invasion of gallbladder carcinoma cell. Conversely, down-expression of miR-1-5p facilitated gallbladder carcinoma cell proliferation and aggressiveness. Mechanistic investigations demonstrated that neurogenic locus notch homolog protein 2 (Notch2) was the directly target of miR-1-5p and Notch2 mediated the inhibitory effect of miR-1-5p in gallbladder carcinoma cell growth and aggressiveness. CONCLUSION: Our findings demonstrated that miR-1-5p acted as a suppressive miRNA and played vital roles in the growth, migration and invasion of gallbladder carcinoma cell through targeting Notch2.
- Roles of Pin1 as a Key Molecule for EMT Induction by Activation of STAT3 and NF-κB in Human Gallbladder Cancer
Annals of surgical oncology 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30610554
BACKGROUND: Despite developments in multidisciplinary treatment, the prognosis for advanced gallbladder cancer (GBC) still is poor because of its rapid progression. Epithelial-mesenchymal transition (EMT) plays a central role in promoting tumor invasion and metastasis in malignancies thorough signal transducer and activator of transcription-3 (STAT3) and nuclear factor κB (NF-κB) activation. Whereas Pin1 mediates STAT3 and NF-κB activation, the involvement of Pin1 in GBC progression is unclear. METHODS: Factors regulating Pin1-related STAT3 and NF-κB activation were evaluated using surgical specimens collected from 76 GBC patients, GBC cells, and orthotopic GBC xenograft mice. RESULTS: In the patients with GBC, high Pin1 expression in GBC was associated with aggressive tumor invasion and increased tumor metastasis, and was an independent factor for a poor prognosis. Pin1 expression was correlated with phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276), thereby activating STAT3 and NF-κB in GBC. Pin1-mediated STAT3 and NF-κB activation induced EMT in GBC. When Pin1 knockdown was performed in GBC cells, the phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276) was inhibited, and STAT3 and NF-κB activation was suppressed. Inactivation of STAT3 and NF-κB in Pin1-depleted cells decreased snail and zeb-2 expression, thereby reducing the rate of mesenchymal-like cells, suggesting that EMT was inhibited in GBC cells. PiB, a Pin1-specific inhibitor, inhibited EMT and reduced tumor cell invasion by inactivating STAT3 and NF-κB in vitro. Moreover, PiB treatment inhibited lymph node metastasis and intrahepatic metastasis in orthotopic GBC xenograft tumor in vivo. CONCLUSIONS: Pin1 accelerates GBC invasion and metastasis by activating STAT3 and NF-κB. Therefore, Pin1 inhibition by PiB is an excellent therapy for GBC by safely inhibiting its metastasis.
- Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes
Cancer 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30620386
BACKGROUND: Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Pathogenic germline alterations (PGAs) in BRCA2 and potentially targetable somatic alterations (SAs) in ERBB2 and ELF3 have been previously described in AC. Memorial Sloan Kettering Cancer Center has implemented an opt-in strategy for germline testing (GT) and somatic testing (ST) for patients with AC to further evaluate the spectrum of PGAs and SAs. METHODS: Forty-five patients with pathologically confirmed AC prospectively consented with the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) test (410-468 genes). A subset of the cohort (23 of the 45 patients) also consented to GT with MSK-IMPACT (76-88 genes). Germline data for 21 of the remaining 22 patients who had not consented to GT were obtained in a de-identified fashion without clinical correlation. Clinicopathologic features, treatment histories, and survival data for consenting patients were collected and analyzed. RESULTS: Pancreaticobiliary, intestinal, and mixed features of the 2 types were the primary pathologic subtypes of AC identified in this cohort. No difference in median overall survival was found between pathologic subtypes. Eight of 44 patients (18%) were identified as harboring pathogenic mutations in BRCA2, ATM, RAD50, and MUTYH. In addition, this study found a wide spectrum of SAs in genes such as KRAS, MDM2, ERBB2, ELF3, and PIK3CA. Two patients in the cohort underwent SA-targeted therapy, and 1 had a partial radiographic response. CONCLUSIONS: Mutations in multiple somatic and germline genes were identified in this cohort. Significantly, actionable targets were identified in the tumors, and broader testing for PGAs and SAs should be considered for all patients with AC.
- The Molecular and Clinical Landscape of Pancreatic Neuroendocrine Tumors
Pancreas 2019 Jan;48(1):9-21
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531241
Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.
- Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors
Cancer 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30620390
BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.
- Pseudomyxoma Peritonei After a Total Pancreatectomy for Intraductal Papillary Mucinous Neoplasm With Colloid Carcinoma in Lynch Syndrome
Pancreas 2019 Jan;48(1):135-138
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531244
We report a case of pseudomyxoma peritonei (PMP) arising in a 62-year-old male patient with Lynch syndrome (LS). The patient’s medical history included an adenocarcinoma of the colon for which a right hemicolectomy was performed and a pancreatectomy due to an intraductal papillary mucinous neoplasm (IPMN) with invasive colloid carcinoma. It was considered that the PMP could be a metastasis of the earlier colonic or pancreatic carcinoma. The pancreatic carcinoma, colon carcinoma, and PMP tissues were examined, and immunohistochemical and molecular analyses were performed to determine the PMP origin. Histopathologic examination revealed morphological similarities with the pancreatic colloid carcinoma, and further immunohistochemical and molecular analyses, including a shared GNAS mutation, confirmed the pancreatic origin of the PMP. In conclusion, this is a unique case of a patient with LS presenting with PMP originating from an IPMN with invasive colloid carcinoma, several years after pancreatectomy. The present case has important diagnostic implications. The IPMN should be considered as a rare extracolonic manifestation of LS, and pancreatic carcinoma origin should be considered in patients presenting with PMP. This case report highlights the added value of molecular diagnostics in daily pathology practice.
- Mucoepidermoid Carcinoma of the Gallbladder: A Case-Based Study of an Extremely Rare Tumor Highlighting the Role of Immunohistochemical Profiling
International journal of surgical pathology 2018 Dec;():1066896918821436
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30587051
Mucoepidermoid carcinoma (MEC) is rarely reported in the hepatobiliary system. In this article, we detail the first case of MEC arising from the gallbladder, presenting in a 50-year-old male. Imaging and gross examination showed a large mass in the gallbladder fossa infiltrating the liver. This microscopically displayed the classical morphology of MEC, which was confirmed on dual immunostain for p63 and CK7 and histochemical staining for mucin. MUC and p53 immunoexpression patterns suggested a poor prognosis. The patient succumbed to the disease with liver metastasis within 6 months. The cytomorphology of the metastatic lesion is also presented. Differences in the stem cell niches in the gallbladder and the rest of the biliary tract may possibly indicate the reason for the rarity of this tumor in the gallbladder. A possibly aggressive biological behavior of the gallbladder MEC necessitates its distinction from entities like the adenosquamous carcinoma.
- Combination of Adenomyoma and Adenomyomatous Hyperplasia of the Ampullary System: A First Case Report
International journal of surgical pathology 2018 Oct;26(7):644-648
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29618230
Adenomyoma and adenomyomatous hyperplasia are benign tumor-like lesions that rarely involve the major or minor duodenal papilla. We report the case of a 73-year-old patient who underwent a cephalic duodenopancreatectomy due to clinical and radiological evidence of underlying malignant neoplasm. The histopathology results revealed the unusual association of a major duodenal papilla adenomyoma and an adenomyomatous hyperplasia of the minor papilla. Because of their resemblance to pancreatic malignancy, the diagnosis of these lesions is particularly challenging. In most cases, it is established postoperatively, after histopathological examination of the surgical specimen.
- Pancreatic Mass in a Patient with a History of Resected Renal Cell Carcinoma and Resected Adenocarcinoma of the Ampulla of Vater: A Case Report
Journal of pancreatic cancer 2018 08;4(1):41-44
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30631857
Background: Metastases of renal cell carcinoma (RCC) to the pancreas are rare, whereas recurrence of pancreatic ductal adenocarcinoma (PDA) or a primary periampullary cancer is far more common. The time elapsed between a primary tumor and a new mass can aid in differentiation between the two. Presentation: A 70-year-old man with a history of RCC status after left nephrectomy and ampullary adenocarcinoma status after pancreaticoduodenectomy presents with an incidentally found mass in his remnant pancreas. Resection of the mass via completion pancreatectomy yielded pathology consistent with metastatic RCC. Conclusions: Metastases of RCC to the pancreas often present many years after a primary resection. Conversely, recurrent PDA often presents within 5 years of resection. Resection of RCC metastases yields better survival than resection of recurrent PDA, which is controversial. We recommend resection of suspected isolated pancreatic RCC metastases due to known favorable outcomes.
- Duodenal somatostatinoma presenting as obstructive jaundice with the coexistence of a gastrointestinal stromal tumour in neurofibromatosis type 1: a case with review of the literature
BMJ case reports 2019 Jan;12(1):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30635305
Somatostatinomas are rare neuroendocrine tumours, mostly located in the pancreas or duodenum, with an estimated incidence of 1 in 40 million. Duodenal somatostatinomas (DSs) are usually found in association with neurofibromatosis type 1 (NF1), tuberous sclerosis and Von Hippel-Lindau syndrome. Gastrointestinal stromal tumours (GIST) have also been described in NF1, but the association with somatostatinoma is very uncommon. We report the case of a patient with NF1 who presented with obstructive jaundice due to multiple firm nodules around the ampulla of Vater. A pancreaticoduodenectomy was performed and revealed a 1 cm duodenal/ampullary mass which stained positive for somatostatin, together with a GIST also found on the duodenal wall. Despite its rarity, ampullary somatostatinomas should be considered in the differential diagnosis of biliary tract dilation in patients with NF1.
- Cell‑to‑cell communication via extracellular vesicles among human pancreatic cancer cells derived from the same patient
Molecular medicine reports 2018 Oct;18(4):3989-3996
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30106154
Despite existing multimodal therapies, pancreatic cancer exhibits high metastatic capability and poor prognosis. Extracellular vesicles (EVs) are nanoparticles comprising lipid bilayers and various other components, such as protein and nucleic acids, derived from secreted cells. Recent research has demonstrated the involvement of EVs released from cancer cells in the metastasis of cancer cells to distant organs. However, the effects of EVs released from pancreatic cancer cells on other pancreatic cancer cells in a tumor microenvironment remain unclear. The present study aimed to elucidate that EVs released from PK‑45H pancreatic cancer cells are taken up by PK‑45P pancreatic cancer cells derived from the same patient through dynamin‑related endocytosis. Additionally, EVs released from PK‑45H cells augment the phosphorylation of classical mitogen‑activated protein kinase (MAPK) pathways in PK‑45P cells. The uptake of EVs released from PK‑45H cells by PK‑45P cells stimulates cell migration through the classical MAPK‑dependent pathway, suggesting that EVs released from one pancreatic cancer cell are taken up by other surrounding pancreatic cancer cells and could be critical inducers of cancer metastasis in the tumor microenvironment.
- Coordinately targeting cell cycle checkpoint functions in integrated models of pancreatic cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30538111
PURPOSE: Cancer cells often have deficiencies in cell cycle control mechanisms and could be dependent on specific cell cycle checkpoints to maintain viability. Due to the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined mechanisms of resistance. EXPERIMENTAL DESIGN: Single agent efficacy of CHK1 inhibition was investigated in established and primary PDAC lines. Drug screening was performed to identify cooperative agents. In vitro and in vivo studies were employed to interrogate combination treatment efficacy and mechanisms of resistance. RESULTS: Many PDAC models evade single agent inhibition through mechanisms that allow S-phase progression with CHK1 inhibited. Gene expression analysis revealed FOXM1 as a potential marker of CHK1 sensitivity and defined a form of pancreatic cancer with poor prognosis. Drug screen analysis identified WEE1 as a cooperative agent with CHK1 and was effective in cell culture. In vivo experiments validated the combination efficacy; however, resistance could evolve. Resistance was due to selection of a stable sub-clone from the original PDX tumor, which harbored high baseline replication stress. In vitro analysis revealed that gemcitabine could eliminate viability in the resistant models. The triplet regimen of gemcitabine, CHK1 and WEE1 inhibition provided strong disease control in all xenograft models interrogated. CONCLUSIONS: These results demonstrate the therapeutic resiliency of pancreatic cancer and indicate that coordinately targeting cell cycle checkpoints in concert with chemotherapy could be particularly efficacious.
- IQGAP1 Maintains Pancreatic Ductal Adenocarcinoma Clonogenic Growth and Metastasis
Pancreas 2019 Jan;48(1):94-98
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30540680
OBJECTIVES: IQ motif containing GTPase-activating protein 1 (IQGAP1) acts as a scaffold for aberrant mitogen-activated protein kinase (MAPK) signaling driven by KRAS mutations in pancreatic ductal adenocarcinoma (PDAC). We determined the role of IQGAP1 in clonogenic growth and metastasis in PDAC. METHODS: We inhibited IQGAP1 expression using shRNA and assessed clonogenic growth, cell migration, and MAPK signaling in vitro and tumor initiation and metastasis in vivo. The efficacy of a peptide mimicking the IQGAP1 WW domain that binds and inhibits ERK1/2 was determined in vitro and in vivo. RESULTS: IQGAP1 loss inhibited clonogenic growth and migration of KRAS-dependent PDAC cells by disrupting MAPK signaling. In mice, IQGAP1 knockdown decreased tumor-initiating cell frequency and metastasis. WW peptide treatment inhibited clonogenic growth and in vivo tumor growth. CONCLUSIONS: Pancreatic ductal adenocarcinoma clonogenic growth, metastasis, and tumor initiation are dependent on MAPK signaling via IQGAP1. Treatment with a WW peptide disrupts IQGAP1 function and represents a novel targeting strategy for PDAC.
- Immunosuppressive βig-h3 links tumour stroma and dysfunctional T cells in pancreatic cancer
Gut 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30530506
- Spontaneous Regression of Metastatic Pancreatic Cancer: A Role for Recurrent Inflammation
Pancreas 2019 Jan;48(1):e4-e6
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531247
- Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in vitro and in vivo
Oncology reports 2018 Dec;40(6):3501-3510
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30272364
Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF‑1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF‑1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real‑time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF‑1α was significantly upregulated in GBC tissues. HIF‑1α overexpression was closely associated with lymph node metastasis and tumor‑lymph node‑metastasis (TNM) stages. HIF‑1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC‑SD cells, an effect which was partly reversed by small‑interfering RNA HIF‑1α (siHIF‑1α) and 2‑methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia‑induced migration via HIF‑1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF‑1α and VEGF in a GBC‑SD cell xenograft model. Taken together, these results suggest that HIF‑1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF‑1α/VEGF pathway.
Techniques, Research Methods, Liquid Biopsy
- Circulating Tumor Cells and Cell-Free DNA in Pancreatic Ductal Adenocarcinoma
The American journal of pathology 2019 Jan;189(1):71-81
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558725
Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and potentially allow for personalized treatment would be of great benefit. This review analyzes the literature regarding two potential biomarkers, circulating tumor cells (CTCs) and cell-free DNA (cfDNA), with regard to pancreatic ductal adenocarcinoma. The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of CTCs and analyzing their molecular characteristics and how they may affect survival in both advanced and early disease and allow for treatment monitoring. The origin of cfDNA is discussed, and the literature over the past 15 years is summarized. This includes analyzing cfDNA for genetic mutations and methylation abnormalities, which have the potential to be used for the detection and prognosis of pancreatic ductal adenocarcinoma. However, the research certainly remains in the experimental stage, warranting future large trials in these areas.
- Emerging Evidence for the Clinical Relevance of Pancreatic Cancer Exosomes
Pancreas 2019 Jan;48(1):1-8
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531240
The last 5 years have seen a dramatic increased interest in the field of exosome biology. Although much is unknown about the role of exosomes in human health and disease, disparate scientific disciplines are recognizing the highly conserved role that exosomes play in fundamental biological processes. Recently, there have been intriguing discoveries defining the role of exosomes in cancer biology. We performed a structured review of the English-language literature using the PubMed database searching for articles relating to exosomes and pancreatic ductal adenocarcinoma (PDAC). Articles were screened for relevance and content to judge for inclusion. Evidence implicates exosomes in the pathogenesis, local progression, metastasis, immune evasion, and intercellular communication of PDAC. Basic science discoveries in exosome biology have the potential to change the clinical management of PDAC, where, despite advances in early detection, diagnosis, staging, chemotherapy, and surgery, survival rates have been stagnant for decades and PDAC remains the most deadly human gastrointestinal malignancy.
- Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors
Translational oncology 2019 Jan;12(1):180-189
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30554606
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.
- Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts
Gastrointestinal endoscopy 2018 07;88(1):79-86
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29510146
BACKGROUND AND AIMS: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology. METHODS: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS-FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis. RESULTS: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%). CONCLUSION: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis.
- Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging
Proteomics. Clinical applications 2018 Dec;():e1800046
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30548962
PURPOSE: To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). EXPERIMENTAL DESIGN: Ninety-three pDAC and 126 pNET individual tissues are assembled in tissue microarrays and analyzed by MALDI MSI. The cohort is separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions is performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC are analyzed by the same LDA algorithm. RESULTS: Classification of pDAC and pNET by the LDA model is correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC are also correctly classified in agreement with the histopathological diagnosis. CONCLUSION AND CLINICAL RELEVANCE: In the present study, a large dataset of pDAC and pNET by MALDI MSI is investigated, a class prediction model that allowed separation of both entities with high accuracy is developed, and differential peptide peaks with potential diagnostic, prognostic, and predictive values are highlighted.
- Is it time to reconsider the principles of pancreatic cancer surgery?
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30553775
- Molecular Profiling of Pancreatic Cancer Patients-Letter
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Dec;24(24):6611
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30552236
- Molecular Profiling of Pancreatic Cancer Patients-Response
Clinical cancer research : an official journal of the American Association for Cancer Research 2018 Dec;24(24):6612
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30552237
- Closing the Disparity in Pancreatic Cancer Outcomes: A Closer Look at Nonmodifiable Factors and Their Potential Use in Treatment
Pancreas 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30629027
OBJECTIVES: African Americans (AAs) have disproportionately higher incidence and lower survival rates from pancreatic cancer compared with whites. Historically, this disparity has been attributed to modifiable risk factors. Recent studies suggest that nonmodifiable aspects may also play an important role. We review these new contributions as potential targets for closing the disparity. METHODS: A PubMed search was conducted to review studies of nonmodifiable elements contributing to pancreatic cancer disparities in AAs. RESULTS: Several nonmodifiable risks are associated with the racial disparity in pancreatic cancer. SSTR5 P335L, Kaiso, and KDM4/JMJD2A demonstrate differential racial expression, increasing their potential as therapeutic targets. Many social determinants of health and their associations with diabetes, obesity, and the microbiome are partially modifiable risk factors that significantly contribute to outcomes in minorities. Barriers to progress include the low minority inclusion in research studies. CONCLUSIONS: Genomics, epigenetics, the microbiome, and social determinants of health are components that contribute to the pancreatic cancer disparity in AAs. These factors can be researched, targeted, and modified to improve mortality rates. Closing the disparity in pancreatic cancer will require an integrated approach of personalized medicine, increased minority recruitment to studies, and advanced health care/education access.
- Immune defects in pancreatic cancer
Annals of pancreatic cancer 2018 Dec;1():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30613834
Pancreatic cancer is resistant to the immunotherapy. This resistance is caused by any of the four immune “defects” that occur in pancreatic cancer, including lack of “high quality” T cells, stromal barriers to T cells getting access to tumor cells, immunosuppressive cells such as M2 macrophages, myeloid derivative suppressor cells, and T regulatory cells, in the tumor microenvironment of pancreatic cancer. One or more defects may occur in an individual pancreatic cancer. To overcome the resistance to the immunotherapy such as immune checkpoint inhibitors, a rational combination of agents that target multiple immune defects is highly demanded.
- Metabolic Dependencies in Pancreatic Cancer
Frontiers in oncology 2018 12;8():617
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30631752
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain.
- Antipancreatic cancer effect of DNT cells and the underlying mechanism
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30579733
OBJECTIVES: This study aimed to explore double-negative T (DNT) cell cytotoxicity to pancreatic cancer and the effect of the Fas (CD95, APO-1)/FasL (CD178) signaling pathway on this process. METHODS: DNT cells from the peripheral blood of healthy volunteers were expanded in vitro. The inhibitory effect of DNT cells on pancreatic cancer cells was investigated using a CCK-8 assay and nude mouse tumor model. A mechanistic study was performed using pathway blocking assays. RESULTS: DNT cells were amplified in vitro with >90% purity, and the growth of pancreatic cancer in vitro was significantly inhibited by DNT cells. After coculture with DNT cells, Fas, caspase-8 and cleaved caspase-8 showed increased expression in pancreatic cancer cells. When blocking agent decoy receptor 3 (DcR3) was added, the antitumor effect of DNT cells and the expression of Fas, caspase-8 and cleaved caspase-8 were reduced in pancreatic cancer cells. In the nude mouse tumor model, the tumor volume and weight were lower in the DNT cell group and gemcitabine group than in the blank control group. Additionally, the expression of Fas, caspase-8 and cleaved caspase-8 was higher in the DNT cell group than in the blank control group. Moreover, DNT cells promoted apoptosis in cancer cells and animal model tissues. CONCLUSION: DNT cells inhibited the growth of pancreatic cancer, and the Fas/FasL signaling pathway was involved in this process.
- Circulating interleukin-6 is associated with disease progression, but not cachexia in pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30497874
BACKGROUND: Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression. METHODS: We retrospectively studied 136 subjects with biopsy-proven pancreatic ductal adenocarcinoma (PDAC), considering the high prevalence of cachexia is this population. Clinical data were abstracted from subjects in all cancer stages, and plasma IL-6 levels were measured using a multiplex array and a more sensitive ELISA. Data were evaluated with univariate comparisons, including Kaplan-Meier survival curves, and multivariate Cox survival models. RESULTS: On multiplex, a total of 43 (31.4%) subjects had detectable levels of plasma IL-6, while by ELISA all subjects had detectable IL-6 levels. We found that increased plasma IL-6 levels, defined as detectable for multiplex and greater than median for ELISA, were not associated with weight loss at diagnosis, but rather with the presence of metastasis (p < 0.001 for multiplex and p = 0.007 for ELISA). Further, while >5% weight loss was not associated with worse survival, increased plasma IL-6 by either methodology was. CONCLUSION: Circulating IL-6 levels do not correlate with cachexia (when defined by weight loss), but rather with advanced cancer stage. This suggests that IL-6 may mediate wasting, but should not be considered a diagnostic biomarker for PDAC-induced cachexia.
- Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer
Annals of surgical oncology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30569296
BACKGROUND: Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients. METHODS: The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed. RESULTS: Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70 ng/ml) than in the HRIs (17.52 ± 6.23 ng/ml). At a level of ≥ 29.8 ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8 ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs. CONCLUSIONS: TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.
- A Glimmer of Hope for Pancreatic Cancer
The New England journal of medicine 2018 Dec;379(25):2463-2464
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30575492
- FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer
The New England journal of medicine 2018 Dec;379(25):2395-2406
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30575490
BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
- The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy over CA19-9 in Pancreatic Cancer Diagnosis
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jan;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30617132
PURPOSE: The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA is a biomarker for PDAC that improves upon CA19-9. EXPERIMENTAL DESIGN: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case/control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set. RESULTS: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and two versions of the sTRA assay, and another optimized for sensitivity, which included two sTRA assays. Both panels achieved statistical improvement (p < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (p < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared to 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker. CONCLUSIONS: sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.
- Familial Pancreatic Ductal Adenocarcinoma
The American journal of pathology 2019 Jan;189(1):36-43
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558720
Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited pancreatic cancer syndromes and familial pancreatic cancer, which together compose up to 10% of PDAC. Understanding the methods and targets of PDAC screening in high-risk individuals may translate to improved morbidity and mortality.
- Current Approaches to Pancreatic Cancer Screening
The American journal of pathology 2019 Jan;189(1):22-35
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30558719
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 8% and is estimated to be the second leading cause of cancer-related deaths by 2021. Prior convention held that screening for PDAC would not be beneficial; however, a deeper understanding of the carcinogenesis pathway supports a potential window of opportunity among the target population. Screening for PDAC is not a standard practice among the general population because of its low incidence. However, screening may be beneficial for individuals with familial history, chronic diseases with genetic predispositions, or inherited cancer syndromes, such as hereditary breast ovarian cancer syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome (hereditary nonpolyposis colorectal cancer), ataxia telangiectasia, and Li-Fraumeni syndrome, all of which have been associated with an increased risk of developing PDAC. The screening strategies among these high-risk individuals are targeted to identify precursor lesions and PDAC at an early resectable stage. This review describes the risk factors for pancreatic cancer, especially the genetic risk factors in high-risk individuals and current screening strategies available for PDAC.
- Dietary Fiber and the Risk of Pancreatic Cancer
Pancreas 2019 Jan;48(1):121-125
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30489447
OBJECTIVES: High dietary fiber may protect against pancreatic ductal adenocarcinoma (PDAC). We investigated associations between fiber intake and the risk of PDAC using for the first time 7-day food diaries. METHODS: Participants in the European Prospective Investigation Into Cancer-Norfolk completed the 7-day food diaries at recruitment. The cohort was followed up for 17 years to identify those who developed PDAC. Participants were divided into quintiles of fiber intake, and hazard ratios (HR) were estimated with their 95% confidence intervals (CIs). Fiber was tested for effect modification of high red and processed meat intake and smoking and the risk of PDAC. RESULTS: No significant associations for any quintiles of intake (HR Q5 vs Q1, 1.08; 95% CI, 0.56-2.08) were detected with no trend across quintiles. A high-fiber diet modified positive associations between red and processed meats with the development of PDAC (HR trends, 0.89 [95% CI, 0.47-1.69] and 1.02 [95% CI, 0.55-1.88], respectively) but not those with lower fiber intake. Fiber intake did not modify the risk of PDAC in past and current smokers. CONCLUSION: The findings do not suggest that fiber protects against PDAC, although it may decrease potential deleterious effects of meats.
- Nomogram to Predict Cancer-Specific Survival in Patients with Pancreatic Acinar Cell Carcinoma: A Competing Risk Analysis
Journal of Cancer 2018 10;9(22):4117-4127
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30519311
Background: The objective of this study was to evaluate the probability of cancer-specific death of patients with acinar cell carcinoma (ACC) and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) of these patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with ACC between 2004 and 2014 were retrospectively collected. Cancer-specific mortality and competing risk mortality were evaluated. Nomograms for estimating 1-, 2- and 3-year OS and CSS were established based on Cox regression model and Fine and Grey’s model. The precision of the 1-, 2- and 3-year survival of the nomograms was evaluated and compared using the area under receiver operating characteristic (ROC) curve (AUC). Results: The study cohort included 227 patients with ACC. The established nomograms were well calibrated, and had good discriminative ability, with a concordance index (C-index) of 0.742 for OS prediction and 0.766 for CSS prediction. The nomograms displayed better discrimination power than 7th or 8th edition Tumor-Node-Metastasis (TNM) stage systems in training set and validation set for predicting both OS and CSS. The AUC values of the nomogram predicting 1-, 2-, and 3-year OS rates were 0.784, 0.797 and 0.805, respectively, which were higher than those of 7th or 8th edition TNM stage systems. Regard to the prediction of CSS rates, the AUC values of the nomogram were also higher than those of 7th or 8th edition TNM stage systems. Conclusion: We evaluated the 1-, 2- and 3-year OS and CSS in patients with ACC for the first time. Our nomograms showed relatively good performance and could be considered as convenient individualized predictive tools for prognosis.
- Systematic review and meta-analysis: Prevalence of incidentally detected pancreatic cystic lesions in asymptomatic individuals
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30503370
BACKGROUND & AIMS: Pancreatic cystic lesions (PCLs) are frequent incidental findings. As most PCLs require costly diagnostic evaluation and active surveillance, it is important to clarify their prevalence in asymptomatic individuals. We therefore aimed at performing a systematic review and meta-analysis to determine it. METHODS: a systematic search was conducted and studies meeting inclusion criteria were included. The prevalence of PCLs was pooled across studies. A random effect model was used with assessment of heterogeneity. RESULTS: 17 studies, with 48,860 patients, were included. Only 3 were prospective; 5 studies were conducted in the US, 7 in Europe, 4 in Asia and 1 in Brazil. The pooled prevalence of PCLs was 8% (95% CI 4-14) with considerable heterogeneity (I2 = 99.5%). This prevalence was higher in studies of higher quality, examining older subjects, smaller cohorts, and employing MRCP (24.8% vs 2.7% with CT-scan). The pooled rate of PCLs was four times higher in studies conducted in the US than in Asia (12.6% vs 3.1%). 7 studies reported the prevalence of mucinous lesions, with a pooled rate of 4.3% (95% CI 2-10; I2 = 99.2%), but of 0.7% only for worrisome features or high risk stigmata. CONCLUSION: The rate of incidentally detected PCLs is of 8%. Mucinous lesions are the most common incidentally detected PCLs, although they rarely present with potential indication for surgery. The observed different rates in the US and other geographic Areas suggest that different protocols might be necessary to help balancing costs and effectiveness of follow-up investigations in asymptomatic subjects.
- Tumor growth rate of pancreatic serous cystadenomas: Endosonographic follow-up with volume measurement to predict cyst enlargement
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30503637
BACKGROUND: Serous cystadenomas are benign lesions of the pancreas. Usually they are diagnosed incidentally on cross-sectional imaging studies. Endosonography is a valuable tool in the diagnosis and follow-up of these cystic lesions. Given its benign nature, surgical resection is advised only in symptomatic patients. The interval and length of surveillance is not well established. METHODS: A retrospective single center study was done. All the patients with a pancreatic serous cystadenoma sent for an endosonographic evaluation, between December 2008 and December 2015 were included. The lesions were follow-up endosonographically at least once, in a 12 months interval. Volume was measured with the formula π/6 × (d1 x d1 x d2). Two groups were evaluated: patients with a volume under 10 mL (Group 1) and those with a volume of 10 mL or more at presentation (Group 2). Growth rate between these two groups was compared. RESULTS: Thirty-one patients were analyzed, with a mean age of 58.2 years. Patients were mainly women (87%). Twenty-four patients in Group 1 had a mean enlargement of 0.67 ml per year, whereas patients in Group 2 had a mean enlargement of 9.8 ml per year. The growth rate difference between these two groups was statistically significant (p = 0.0001). CONCLUSION: Asymptomatic patients with pancreatic serous cystadenomas should be follow-up for enlargement. Small volume lesions have a low risk of enlargement compared with high volume and macrocystic serous cystadenomas. Volume at presentation is a feature to analyze when defining surveillance interval.
- Pancreatic Cancer: A Rare Cause of Abdominal Pain in Severe Cystic Fibrosis
Pancreas 2019 Jan;48(1):e3-e4
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30531246
- Results of First-round of Surveillance in Individuals at High-risk of Pancreatic Cancer from the AISP (Italian Association for the Study of the Pancreas) Registry
The American journal of gastroenterology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30538291
INTRODUCTION: Surveillance programs on high-risk individuals (HRIs) can detect pre-malignant lesions or early pancreatic cancer (PC). We report the results of the first screening round of the Italian multicenter program supported by the Italian Association for the study of the Pancreas (AISP). METHODS: The multicenter surveillance program included asymptomatic HRIs with familial (FPC) or genetic frailty (GS: BRCA1/2, p16/CDKN2A, STK11/LKB1or PRSS1, mutated genes) predisposition to PC. The surveillance program included at least an annual magnetic resonance cholangio pancreatography (MRCP). Endoscopic ultrasound (EUS) was proposed to patients who refused or could not be submitted to MRCP. RESULTS: One-hundreds eighty-seven HRIs underwent a first-round screening examination with MRCP (174; 93.1%) or EUS (13; 6.9%) from September 2015 to March 2018.The mean age was 51 years (range 21-80).One-hundreds sixty-five (88.2%) FPC and 22 (11.8%) GF HRIs were included. MRCP detected 28 (14.9%) presumed branch-duct intraductal papillary mucinous neoplasms (IPMN), 1 invasive carcinoma/IPMN and one low-grade mixed-type IPMN, respectively. EUS detected 4 PC (2.1%): 1 was resected, 1 was found locally advanced intraoperatively, and 2 were metastatic. Age > 50 (OR 3.3, 95%CI 1.4-8), smoking habit (OR 2.8, 95%CI 1.1-7.5), and having > 2 relatives with PC (OR 2.7, 95%CI 1.1-6.4) were independently associated with detection of pre-malignant and malignant lesions. The diagnostic yield for MRCP/EUS was 24% for cystic lesions. The overall rate of surgery was 2.6% with nil mortality. DISCUSSION: The rate of malignancies found in this cohort was high (2.6%). According to the International Cancer of the Pancreas Screening Consortium the screening goal achievement was high (1%).
- Incidence Trends of Gastroenteropancreatic Neuroendocrine Tumors in the United States
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30580091
BACKGROUND & AIMS: Although multiple studies have reported an increasing incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) over the past decades, there are limited national data on recent trends. Using a population-based registry, we evaluated GEP-NET incidence trends in the United States population from 1975 through 2012, based on age, calendar year at diagnosis, and year of birth. METHODS: GEP-NET cases from 1975 through 2012 were identified from the most recent version of the Surveillance, Epidemiology, and End Results registry using histologic and site codes. We calculated overall annual incidence, age-adjusted incidence (number of cases per 100,000), annual percent change (APC), and average APC by 5-year age intervals. We also evaluated the incidence rates by age, period, and birth year cohorts. RESULTS: We identified 22,744 patients with GEP-NETs. In adults 25-39 years old, GEP-NET incidence rates decreased from the mid-1970s to the early 1980s, then increased until 2012. In adults ages 40 years and older or young adults ages 15-24 years, incidence rates generally increased continuously from 1975 through 2012. Adults ages 40-69 years had the most rapid increases in average APC (approximately 4%-6% per year). Overall incidence rates were highest in adults 70-84 years old. Since the inception of the Surveillance, Epidemiology, and End Results registry, GEP-NET incidence has increased in consecutive birth cohorts. CONCLUSION: The incidence of GEP-NET continues to increase-particularly in older adults. More recent generations have had higher GEP-NET incidence rates than more distant generations.
- Global Patterns and Trends in Pancreatic Cancer Incidence: Age, Period, and Birth Cohort Analysis
Pancreas 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30589831
OBJECTIVES: We aim to provide a global geographical picture of pancreatic cancer incidence and temporal trends from 1973 to 2015 for 41 countries. METHODS: Joinpoint regression and age-period-cohort model was used. RESULTS: In 2012, the highest age-adjusted rate was in Central and Eastern Europe for male and North America for female. Most regions showed sex disparities. During the recent 10 years, increasing trends were observed in North America, Western Europe, and Oceania. The greatest increase occurred in France. For recent birth cohorts, cohort-specific increases in risk were pronounced in Australia, Austria, Brazil, Canada, Costa Rica, Denmark, Estonia, France, Israel, Latvia, Norway, Philippines, Republic of Korea, Singapore, Spain, Sweden, the Netherlands, United States, and US white male populations and in Australia, Austria, Brazil, Bulgaria, Canada, China, Czech Republic, Finland, France, Italy, Japan, Lithuania, Norway, Republic of Korea, Singapore, Spain, The Netherlands, United Kingdom, United States, and US white female populations. CONCLUSIONS: In contrast to the favorable effect of the decrease in smoking prevalence, other factors, including the increased prevalence of obesity and diabetes and increased physical inactivity, increased intake of red or processed meat and inadequate intake of fruits and vegetables are likely to have an unfavorable role in pancreatic cancer incidence worldwide.
- Large database utilization in health outcomes research in pancreatic cancer: an update
Journal of gastrointestinal oncology 2018 Dec;9(6):996-1004
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30603118
We sought to review published aggregate dataset studies on pancreatic cancer in the national and international settings, discuss the advantages and disadvantages these datasets possess, and possible future directions. A combination of Google Scholar, PubMed, and MEDLINE were used with search terms “pancreatic cancer” + “resectable” + “national cancer database”, “pancreatic cancer” + “unresectable” + “national cancer database” and more broadly “borderline resectable pancreatic cancer”, “locally advanced pancreatic cancer”, “unresectable pancreatic cancer”, and “resectable pancreatic cancer”. Original articles and abstracts from this search were included, including data from the Surveillance, Epidemiology, and End Results (SEER) database, National Cancer Database (NCDB), and SEER-Medicare within the United States (US), as well as international database studies. Multiple database studies have been published regarding the role for radiotherapy in resected pancreatic cancer (n=6), the timing of additional therapy in resectable pancreatic cancer (n=4), and the role for radiotherapy and resection in locally advanced pancreatic cancer (LAPC) (n=4). Studies from both SEER and NCDB found a survival benefit to post-operative radiotherapy. In resectable pancreatic cancer, neoadjuvant treatment was found to be superior to adjuvant (NCDB). Chemoradiotherapy was found to be more beneficial than chemotherapy alone in LAPC, and patients who received highly-conformal or stereotactic body radiotherapy (SBRT) had improved survival compared to either conformal radiotherapy or chemotherapy alone. These studies also found that up to 10% of patients underwent resection, with a 90% margin-negative rate, and either one-half to one-third the risk of death of non-surgical patients. Criticism of large datasets includes lack of granularity of performance status, diagnosis, treatment, and outcomes-related data compared to properly administered prospective trials, as well as cross-over between treatment arms that cannot be accounted for, and concerns over quality of data represented. The US has witnessed a growing number of comparative effectiveness studies in pancreatic cancer. When taken together, certain themes emerge that are consistent with both single-institution data and clinical trials. These studies have also provided insight into questions not readily answerable by clinical trials. However, they require caution in interpretation.
- EBV as a potential risk factor for hepatobiliary system cancer: A meta-analysis with 918 cases
Pathology, research and practice 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30497878
OBJECTIVES: Hepatobiliary system cancer, which includes hepatocellular carcinoma (HCC), cholangiocarcinoma, and gallbladder carcinoma, has an increase of incidence and mortality due to various risk factors. Epstein-Barr virus (EBV) is associated with various types of lymphomas and carcinomas, which is also acknowledged as the first-discovered human tumor virus. Despite this, there is no systematic analysis about the relationship between the infection of EBV and hepatobiliary system cancer. The aim of this meta-analysis is to explore the significance of EBV infection in the development of hepatobiliary system cancer by evaluating the EBV infection ratio. METHODS: A systematic search of PubMed, Embase, Cochrane Library, as well as China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wan Fang, and China Biology Medicine databases was conducted. The EBV infection ratio and 95% confidence intervals (CIs) in hepatobiliary system cancer was evaluated. The I2 statistic was used to represent heterogeneity. Through meta-regression, stratified analyses were applied to find out heterogeneity’s sources. Odds ratios (ORs), 95% CIs of EBV infection in case-control studies were calculated. RESULTS: Altogether, 15 studies were included containing a total of 918 cases and 157 controls. The whole infection ratio of EBV was 23% (95% CI: 13%, 33%, I2 = 95.7%, P < 0.001) among all the patients. Comparable EVB infection ratios were observed in hepatobiliary system cancer as divided into different subtypes. The five case-control studies were epitomized to a pooled OR of 9.35 (95%CI: 2.95, 29.61, I2 = 20.1%, P < 0.286). CONCLUSION: EBV may be a potentially risk factor in the process of hepatobiliary system cancer. The prospective molecular mechanism remains to be explored.
- Current survival and treatment trends for surgically resected intrahepatic cholangiocarcinoma in the United States
Journal of gastrointestinal oncology 2018 Oct;9(5):942-952
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30505597
Background: Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive disease with an increasing incidence in the United States, and there is no level 1 evidence to help guide treatment decisions. We sought to determine national trends in surgical and medical management of patients with resected ICC, and more specifically, the role of lymphadenectomy (LAD) and utilization of chemotherapy. Methods: An augmented version of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer database registry was used to identify all surgically resected ICC patients from 2000 to 2014. We evaluated the incidence and adequacy of LAD, and receipt of chemotherapy over time. Next, multivariable logistic regressions were performed to determine the predictors of LAD and receipt of chemotherapy. Overall survival (OS) was evaluated using Kaplan-Meier and Cox proportional hazard models. Results: We identified 1,263 patients who underwent resection for ICC. Lymph nodes (LNs) were removed in 49% of patients, however, only 10% of patients received adequate LAD by the American Joint Committee on Cancer (AJCC) criteria (≥6 nodes). LN metastases were found in 29% of patients who underwent nodal evaluation. Chemotherapy was administered to 40% of patients, was utilized more frequently over time (P<0.05), and was associated with improved survival in node positive patients (P<0.05). Patients who did not have LNs evaluated were significantly less likely to receive chemotherapy than those who did. Lastly, OS for the entire cohort improved over time (P<0.05). Conclusions: After analyzing the treatment and outcomes of resectable ICC, we concluded: (I) LN evaluation at the time of surgical resection remains inadequate; (II) utilization of chemotherapy has increased over time; (III) the lack of LAD likely results in under-staging and underutilization of chemotherapy; and (IV) despite less than ideal surgical and medical therapy median OS continues to improve.
- Actual 5-Year Survivors After Surgical Resection of Hilar Cholangiocarcinoma
Annals of surgical oncology 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30539494
BACKGROUND: The prevalence and characteristics of actual 5-year survivors after surgical treatment of hilar cholangiocarcinoma (HC) have not been described previously. METHODS: Patients who underwent resection for HC from 2000 to 2015 were analyzed through a multi-institutional registry from 10 U.S. academic medical centers. The clinicopathologic characteristics and both the perioperative and long-term outcomes for actual 5-year survivors were compared with those for non-survivors (patients who died within 5 years after surgery). Patients alive at last encounter who had a follow-up period shorter than 5 years were excluded from the study. RESULTS: The study identified 257 patients with HC who underwent curative-intent resection with an actuarial 5-year survival of 19%. Of 194 patients with a follow-up period longer than 5 years, 23 (12%) were 5-year survivors. Compared with non-survivors, the 5-year survivors had a lower median pretreatment CA 19-9 level (116 vs. 34 U/L; P = 0.008) and a lower rate of lymph node involvement (42% vs. 15%; P = 0.027) and R1 margins (39% vs. 17%; P = 0.042). However, the sole presence of these factors did not preclude a 5-year survival after surgery. The frequencies of bile duct resection alone, major hepatectomy, caudate lobe resection, portal vein or hepatic artery resection, preoperative biliary sepsis, intraoperative blood transfusion, serious postoperative complications, and receipt of adjuvant chemotherapy were comparable between the two groups. CONCLUSIONS: One in eight patients with HC reaches the 5-year survival milestone after resection. A 5-year survival can be achieved even in the presence of traditionally unfavorable clinicopathologic factors (elevated CA 19-9, nodal metastasis, and R1 margins).
- Impact of microvascular invasion on clinical outcomes after curative-intent resection for intrahepatic cholangiocarcinoma
Journal of surgical oncology 2019 Jan;119(1):21-29
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30466151
BACKGROUND: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. METHODS: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). RESULTS: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (±MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P < 0.01). On multivariable analysis, MiVI was an independent risk factor of DFS (hazard ratios [HR] 1.5; 95%confidence intervals [CI], 1.3-1.9; P < 0.001), but not OS (HR 1.1; 95%CI, 0.9-1.3; P = 0.379). While MiVI and MaVI patients had similar DFS (median, MiVI 14.0 vs MaVI 12.0 months, HR 0.9; 95%CI, 0.7-1.2; P = 0.377), OS was better among MiVI patients (median, MiVI 39.0 vs MaVI 21.0 months, HR 0.7; 95%CI, 0.5-0.8; P = 0.002). Whereas nodal metastasis, R1 margin, and postoperative morbidity were associated with early death (≤18 months) among patients with MiVI, only nodal metastasis was associated with late (>18 months) prognosis. CONCLUSIONS: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence.
- Signet ring cancer of the gall bladder: a SEER database analysis
Minerva gastroenterologica e dietologica 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30488679
- Risk of Primary Neuroendocrine Pancreatic Tumor After a First Primary Cancer: A US Population-Based Study
Pancreas 2018 Dec;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30589832
OBJECTIVE: This study aimed to describe the relative and excess risk of pancreatic neuroendocrine tumor (NET) at least 6 months after the first primary cancer (FPC) among the US population. METHODS: Surveillance, Epidemiology, and End-Results Program data were analyzed for patients diagnosed as having FPC from 2000 to 2015 (n = 4,008,092). Standardized incidence ratios, excess risk, and average time to diagnosis of a second primary pancreatic NET were reported by FPC site, stratified by sex and receipt of radiotherapy and chemotherapy. RESULTS: Risk of pancreatic NET was significantly higher after FPC at any site, any solid tumor (standardized incidence ratios, 1.3; 95% confidence interval, 1.2-1.5), pancreas, thymus, small intestine, liver, stomach, kidney, lung, and female breast. Excess incidence of pancreatic NET was highest among those with FPC (especially NET) of the pancreas, bladder, thymus, and female breast; those who received radiotherapy/chemotherapy for bladder, melanoma, and stomach cancers; and those who received chemotherapy for uterine, cervical, prostate, and other genital cancers. Time to diagnosis was shortest after pancreatic, liver, lung, and stomach cancer. CONCLUSIONS: Cancer survivors have increased risk and excess incidence of primary pancreatic NET compared with the population, particularly for certain primary sites. High-risk patients should receive regular follow-up screenings, counseling to reduce carcinogen exposure, and lifestyle interventions.
- Prognosis of patients with neuroendocrine tumor: a SEER database analysis
Cancer management and research 2018 11;10():5629-5638
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30519109
Background: Neuroendocrine tumors (NETs) are a group of heterogeneous cancers arising from a variety of anatomic sites. Their incidence has increased in recent years. This study aimed to analyze the prognosis of NETs originating from different anatomic sites. Methods: We identified 73,782 patients diagnosed with NETs from the Surveillance Epidemiology and Ends Results (SEER) database from 1973 to 2014. Clinical data were compared between patients with different primary tumor sites using the chi-squared test. Differences in survival among NET patients with different tumor sites were compared by Kaplan-Meier analysis. Cox proportional hazard models were performed to identify the prognostic factors of overall survival. Results: In this cohort, the lung/bronchus was the most common site of NETs, accounting for 30.6%, followed by the small intestine (22.2%), rectum (16.2%), colon (13.4%), pancreas (10.8%), and stomach (6.8%). Totally, 73,782 patients were selected for this cohort from 1973 to 2014. The median survival duration was 41 months. The 1-, 3-, 5-, and 10-year overall survival rates for patients with NETs were 72.8%, 52.7%, 39.4%, and 18.1%, respectively. Patients with NETs located in the rectum had the best prognosis, followed by those with NETs in the small intestine (HR, 1.660, 95% CI, 1.579, 1.744), lung/bronchus (HR, 1.786, 95% CI, 1.703, 1.874), stomach (HR, 1.865, 95% CI, 1.755, 1.982), and colon (HR, 1.896, 95% CI, 1.799, 1.999). Patients with NETs in the pancreas had the highest risk of mortality (HR, 2.034, 95% CI, 1.925, 2.148). Conclusion: Significant differences in survival were found among various primary tumor sites. NETs in the rectum had the best prognosis, while those in the pancreas had the worst. Primary tumor sites might be one of the most useful outcome predictors in patients with NETs.
- Demographics, tumor characteristics, treatment, and clinical outcomes of patients with ampullary cancer: a surveillance, epidemiology, and end results (SEER) cohort study
Minerva gastroenterologica e dietologica 2018 Nov;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30488680
INTRODUCTION: Ampullary cancer accounts for only 0.2% of GI cancers. The objective of this study was to investigate the incidence, demographics, tumor characteristics, treatment, and survival of patients with ampullary tumors. METHODS: Data on ampullary cancer between 2004 and 2013 was extracted from the Surveillance, Epidemiology and End Results (SEER) Registry. The clinical epidemiology of these tumors was analyzed using SEER*Stat. RESULTS: A total of 6803 patients with ampullary cancer were identified. Median age at diagnosis was 71±13 years. The overall age-adjusted incidence of ampullary cancer was 0.59 per 100,000 per year. A higher incidence of ampullary cancer was observed in males compared to females (0.74 vs 0.48 per 100,000 per year). Most tumors were moderately differentiated (39.5%). The most common stage at presentation was Stage I (21%), followed by Stage II (20%). The majority (63%) of these tumors were surgically resected while 20% of patients received radiotherapy. One and 5-year cause-specific survival for ampullary cancer was 71.7% and 38.8% respectively, with a median survival of 31 months. On Cox regression analysis, Black race, increasing cancer stage and grade, N1 stage, and non-surgical treatment were associated with poorer prognosis. Those who were not treated with surgical intervention were at 4.5 times increased risk for death (Hazard Ration 4.5, 95% CI 3.93-5.09, P=0.000). CONCLUSIONS: The annual incidence of ampullary cancer has been fairly constant, though males are more likely to be affected. While its incidence increases with age, patients who are treated by surgical intervention have significantly better outcomes. Additionally, through the use of endoscopic techniques, ampullary cancer can be detected and treated much earlier.
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